# Example applications¶

## Sorting an ensemble¶

The CREGEN routine that is used within the conformational search can also be used as a standalone tool by including the -cregen flag:

crest struc.xyz -cregen ensemble.xyz


Here ensemble.xyz is the ensemble file that contains all the structures in the Xmol format.

Note

It is required to present a single reference structure (struc.xyz in the example above) of the molecule to check for CN clashes. Also, all structures in the ensemble must have the same atom order.

## Comparing two ensembles¶

Two ensembles generated on different levels of theory can be compared with the -compare option. Let’s assume that there are two ensembles v1.xyz, generated with the MF-MD-GC procedure and v2.xyz, generated with the default iMTD-GC workflow. To compare the 5 lowest conformers of each ensemble simply call:

crest struc.xyz -compare v1.xyz v2.xyz -maxcomp 5

       ==============================================
|                                            |
|                 C R E S T                  |
|                                            |
|  Conformer-Rotamer Ensemble Sampling Tool  |
|        based on the GFN-xTB method         |
|             S.Grimme, P.Pracht             |
|          Universitaet Bonn, MCTC           |
==============================================
Version 2.7, Thu 27. Jun 13:41:37 CEST 2019
Using the GFN-xTB code.
Compatible with XTB version 6.1 and later.

---------------------
Sorting file <v1.xyz>
---------------------
running RMSDs... done.
File <v1.xyz> contains 240 conformers.
The 5 lowest conformers will be taken for the comparison:
conformer  #rotamers
1          1
2          5
3          3
4          1
5          2

---------------------
Sorting file <v2.xyz>
---------------------
running RMSDs... done.
File <v2.xyz> contains 51 conformers.
The 5 lowest conformers will be taken for the comparison:
conformer  #rotamers
1          6
2          4
3          3
4          6
5          4

-----------------------
Comparing the Ensembles
-----------------------
Calculating RMSDs between conformers... done.
RMSD threshold:  0.1250 Å

RMSD matrix:
conformer          1          2          3          4          5
1         0.01727    1.44147    1.56327    0.81845    0.83933
2         0.00791    1.43084    1.56995    0.79512    0.83992
3         1.43350    0.01254    0.80724    1.58138    1.59243
4         0.12794    1.40597    1.54663    0.89315    0.83634
5         0.14626    1.51398    1.56167    0.68473    0.88006

--------------------------------
Correlation between Conformers :
--------------------------------
#     Ensemble A             #    Ensemble B
5     -33.87887
4     -33.87937
3     -33.87947
5      -33.88008
4      -33.88011
3      -33.88017   <---->    2     -33.88016
2      -33.88023   <---->    1     -33.88023
1      -33.88023

-----------------
Wall Time Summary
-----------------
--------------------
Overall wall time  : 0h : 0m : 0s

CREST terminated normally.


From the output it can be seen that there is a correlation between the lowest conformers, i.e., the lowest conformers were found by both workflows. As the display options in the terminal are limited, an additional file called rmsdmatch.dat is written, from which the exact correlation between the conformers of the two ensembles can be read. If, for example, two different levels of theory are used and the energies of the molecules in both ensembles are too different, then the output will not be of much use and one must refer to the rmsdmatch.dat file.

1     1
2     1
3     2


Each line in this file consists of only two values a and b which denote that conformer a from ensemble A matches conformer b from ensemble B. In the example case shown above, the MF-MD-GC produced the lowest conformer twice, which both naturally match conformer 1 from the iMTD-GC procedure. The second conformer is also the same in both ensembles.

Note

For a successful comparison, both ensembles must have the same number of atoms with the same atom order in each structure. Furthermore, the ensembles should be full CREs, i.e., rotamers should be present.

## Constrained conformational sampling¶

Warning

The following application is still under development and should be considered an experimental feature.

It is possible to include additional constraints to all xtb calculations that are conducted by CREST. To do this, one has to create a file called .constrains (or .xcontrol, both are valid) in the working directory, which contains the constraints in the exact same syntax as used by xtb (see section Detailed Input). Constraints that are included via the .constrains file will be included in ALL calculations of the conformer search run. To circumvent name conventions, a constrainment file under an arbitrary name can directly be provided by the -cinp <FILE> option. Since this can overwrite settings created by CREST it should only be used very cautiously!

The main application for the additional constraints is the constrainment (fixing) of atoms, which could for example be used to sample only conformations for parts of a molecule. Another use could be the sampling of conformers for the transition state of a reaction.

To fix atoms, it is also recommended to use a reference input file additionally to the normal structure input file, which is done with the argument reference=FILE in the .xcontrol file. Furthermore, fixed atoms should not be included in the RMSD of the MTD collective variables.

The content of the .xcontrol file for fixing atoms should look like the following example:

$constrain atoms: 4,8,10,12 # atoms 4, 8, 10 and 12 of some example molecule shall be constrained force constant=0.5 reference=coord.original # name of the reference file (just a copy of the input coord-file)$metadyn
atoms: 1-3,5-7,9,11         # atoms *included* to RMSD in the MTD (typically NOT the constrained atoms)
$end  This should ensure correct constrainment (as far as possible) in the MTD, as well as in the GFNn-xTB geometry optimization within a CREST run. It is also possible to let CREST generate such a file automatically. To do this, the list of atoms has to be provided with the flag --constrain <atom list>, i.e., crest struc.xyz --constrain <atom list>  which will not start any calculation but instead write a file .xcontrol.sample that could subsequentially be used. Furthermore, the file coord.ref will be created. (e.g. for a molecule with 65 atoms): crest struc.xyz --constrain 1,2,3,10-13   ============================================== | | | C R E S T | | | | Conformer-Rotamer Ensemble Sampling Tool | | based on the GFN methods | | P.Pracht, S.Grimme | | Universitaet Bonn, MCTC | ============================================== Version 2.11, Tue 13. Jul 16:11:14 CEST 2021 Using the xTB program. Compatible with xTB version 6.4.0 Cite work conducted with this code as P. Pracht, F. Bohle, S. Grimme, PCCP, 2020, 22, 7169-7192. and S. Grimme, JCTC, 2019, 15, 2847-2862. with help from: C.Bannwarth, F.Bohle, S.Ehlert, S.Grimme, P.Pracht, S. Spicher This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. Command line input: > crest struc.xyz --constrain 1,2,3,10-13 Input list of atoms: 1,2,3,10-13 7 of 20 atoms will be constrained. A reference coord file coord.ref was created. The following will be written to <.xcontrol.sample>: >$constrain
>   atoms: 1-3,10-13
>   force constant=0.5
>   reference=coord.ref
> $metadyn > atoms: 4-9,14-20 >$end


Note

Important: <atom list> must not contain any blanks and atoms must be separated by comma. Ranges (e.g. 10-13) are allowed.

## Sampling of noncovalent complexes and aggregates (NCI mode)¶

A specialized application of CREST is the sampling of aggregates (also referred to as NCI mode). The idea here is to find different conformations of noncovalently bound complexes in which the arrangement of the fragments is of interest. The application can be called by:

crest struc.xyz -nci


The procedure and output is essentially the same as a normal iMTD-GC production run, but with reduced settings (less MTDs, different $$k$$ and $$\alpha$$), and no genetic structure crossing. What is different, however, is that first an ellipsoid wall potential is created and added to the meta-dynamics. A nice example for this application are small molecular clusters, e.g. (H2O)6. The ellipsoid potential that is automatically determined for the input cluster is visualized in the figure below.

The ellipsoid potential is required in the MTDs to counteract the bias potential, which would simply lead to a dissociation of the NCI complex after a few picoseconds (due to the maximization of the RMSD). In the subsequent geometry optimization, however, the surrounding potential must not be present since the bias potential is also not there and the structure would be artificially compressed by the ellipsoid. Hence it is automatically removed in the geometry optimizations

Note

The ellipsoid potential can be scaled by the factor REAL with the flag -wscal REAL.

Many new clusters are generated even for small NCI complexes, typically much more than conformers are generated for a single medium-sized molecule. In general, the task of finding new low lying aggregates is much more challenging than finding (only) conformers, since each fragment of the complex could also have several different low lying conformations. For the (H2O)6 cluster 3 examples are shown in the figure below. Note that all three structures are also part of the well-established WATER27 benchmark set, but were generated automatically by CREST from a single input structure. In total 69 different clusters were found of which only 3 are shown.

## Molecular prototropy screening¶

### Protonation site screening¶

The screening for possible protonation sites, i.e., for the different protomers of a molecule is possible by using a localized molecular orbital LMO approach. Herein, first the $$\pi$$- and LP-centers are determined by a GFNn-xTB calculation, and then all possible input structures are generated where a proton is placed at one of these centers. This procedure was first described in J. Comput. Chem. 2017, 38, 2618–2631.

The example calculation is performed for alanineglycine, in the gas phase, with the command

crest struc.xyz -protonate

    ==============================================
|                                            |
|                 C R E S T                  |
|                                            |
|  Conformer-Rotamer Ensemble Sampling Tool  |
|          based on the GFN methods          |
|             P.Pracht, S.Grimme             |
|          Universitaet Bonn, MCTC           |
==============================================
Version 2.11, Tue 13. Jul 16:11:14 CEST 2021
Using the xTB program. Compatible with xTB version 6.4.0

<.......>
__________________________________________
|                                          |
|       automated protonation script       |
|__________________________________________|

<.......>

LMO calculation ... done.

-----------------------
Multilevel Optimization
-----------------------
-------------------------
1. crude pre-optimization
-------------------------
Optimizing all 13 structures from file "protonate_0.xyz" ...
1 2 3 4 5 6 7 8 9 10 11 12 13
done.
12 structures remain within    90.00 kcal/mol window

---------------------
2. loose optimization
---------------------
Optimizing all 12 structures from file "protonate_1.xyz" ...
1 2 3 4 5 6 7 8 9 10 11 12
done.
12 structures remain within    60.00 kcal/mol window

--------------------------------------------
3. optimization with user-defined thresholds
--------------------------------------------
Optimizing all 12 structures from file "protonate_2.xyz" ...
1 2 3 4 5 6 7 8 9 10 11 12
done.
9 structures remain within    30.00 kcal/mol window

===================================================
Identifying topologically equivalent structures:
Equivalent to 2. structure: 7 structure(s).
Done.
Appending file <protonated.xyz> with structures.

Initial 9 structures from file protonate_3.xyz have
been reduced to 3 topologically unique structures.

===================================================
============= ordered structure list ==============
===================================================
written to file <protonated.xyz>

structure    ΔE(kcal/mol)   Etot(Eh)
1            0.00        -33.953296
2            2.33        -33.949576
3           28.73        -33.907516

-----------------
Wall Time Summary
-----------------
LMO calc. wall time :         0h : 0m : 0s
multilevel OPT wall time :         0h : 0m :10s
--------------------
Overall wall time  : 0h : 0m :10s

CREST terminated normally.


As one can see from the output, three possible protomers of alanineglycine were found at the GFN2-xTB level (within the default 30 kcal/mol energy window around the most stable protomer). This ensemble of structures is written to a file called protomers.xyz. The first (lowest) protomer created by CREST for this molecule includes a ring-closure, apparently caused by the addition of the proton. This nicely demonstrates the ability of our approach to form and break new bonds. The three protomers are shown in the figure below.

### Deprotonation site screening¶

The general approach to find deprotonation sites at a GFN level is much more simple than finding protonation sites. For each hydrogen atom in the structure a new (deprotonated) reference structure is created and optimized in a multilevel approach. The commandline argument to invoke this search is listed below. For the example of alanineglycine, again three structures are obtained and written to a file called deprotonated.xyz. However, two of the three structures have much higher energies and therefore mainly the lowest deprotomer should be considered.

crest struc.xyz -deprotonate

<.......>
<.......>

===================================================
============= ordered structure list ==============
===================================================
written to file <deprotonated.xyz>

structure    ΔE(kcal/mol)   Etot(Eh)
1            0.00        -33.597012
2           24.18        -33.558474
3           24.44        -33.558057

<.......>
<.......>


### Tautomerization screening¶

The last application of the different prototropy screening protocols is an automatized tautomerization tool, which utilizes both the protonation and deprotonation procedures presented in the previous two subsections. By first protonating a molecule and then deprotonating the resulting protomers at all postions, prototropic tautomers relative to the initial input structure can be found. A single cycle of this protonation/deprotonation in principle yields all tautomers with a single hydrogen permutation relative to the input. If a higher number of hydrogen permutations is required, the procedure can simply be repeated with the created tautomers, i.e., tautomers with two or more hydrogen atom permutations are generated. From experience, however, it is generally sufficient to repeat this protonation/deprotonation cycle twice (which is the default in CREST), in order to get the relevant low energy tautomers. The approach was first described in J. Comput.-Aided Mol. Des. 2018, 32, 1139-1149. The tautomerization search can be conducted by the command below. The output is generated for alanineglycine.

crest struc.xyz -tautomerize

    ==============================================
|                                            |
|                 C R E S T                  |
|                                            |
|  Conformer-Rotamer Ensemble Sampling Tool  |
|          based on the GFN methods          |
|             P.Pracht, S.Grimme             |
|          Universitaet Bonn, MCTC           |
==============================================
Version 2.11, Tue 13. Jul 16:11:14 CEST 2021
Using the xTB program. Compatible with xTB version 6.4.0

<.......>
__________________________________________
|                                          |
|     automated tautomerization script     |
|__________________________________________|

<.......>

******************************************************************************************
**                   P R O T O N A T I O N   C Y C L E     1 of 2                       **
******************************************************************************************

LMO calculation ... done.
-----------------------
Multilevel Optimization
-----------------------
<.......>
===================================================
Identifying topologically equivalent structures:
<.......>
Appending file <protonated.xyz> with structures.

Initial 10 structures from file protonate_2.xyz have
been reduced to 3 topologically unique structures.
===================================================
============= ordered structure list ==============
===================================================
written to file <protonated.xyz>

structure    ΔE(kcal/mol)   Etot(Eh)
1            0.00        -33.952363
2            1.84        -33.949433
3           28.36        -33.907162

******************************************************************************************
**                 D E P R O T O N A T I O N   C Y C L E     1 of 2                     **
******************************************************************************************
-----------------------
Multilevel Optimization
-----------------------
<.......>
===================================================
Identifying topologically equivalent structures:
<.......>
Appending file <deprotonated.xyz> with structures.

Initial 25 structures from file deprotonate_2.xyz have
been reduced to 8 topologically unique structures.
===================================================
============= ordered structure list ==============
===================================================
written to file <deprotonated.xyz>

structure    ΔE(kcal/mol)   Etot(Eh)
<.......>

******************************************************************************************
**                   P R O T O N A T I O N   C Y C L E     2 of 2                       **
******************************************************************************************
Calculating LMOs for all structures in file <tautomerize_1.xyz>
<.......>
Collecting generated protomers ... done.

-----------------------
Multilevel Optimization
-----------------------
<.......>
===================================================
Identifying topologically equivalent structures:
<.......>
Appending file <protonated.xyz> with structures.

Initial 48 structures from file protonate_1.xyz have
been reduced to 13 topologically unique structures.
===================================================
============= ordered structure list ==============
===================================================
written to file <protonated.xyz>

structure    ΔE(kcal/mol)   Etot(Eh)
<.......>

******************************************************************************************
**                 D E P R O T O N A T I O N   C Y C L E     2 of 2                     **
******************************************************************************************
-----------------------
Multilevel Optimization
-----------------------
<.......>
===================================================
Identifying topologically equivalent structures:
<.......>
Appending file <deprotonated.xyz> with structures.

Initial 77 structures from file deprotonate_2.xyz have
been reduced to 17 topologically unique structures.
===================================================
============= ordered structure list ==============
===================================================
written to file <deprotonated.xyz>

structure    ΔE(kcal/mol)   Etot(Eh)
<.......>

******************************************************************************************
**                              T A U T O M E R I Z E                                   **
******************************************************************************************
---------------------------
Final Geometry Optimization
---------------------------
<.......>
===================================================
Identifying topologically equivalent structures:
Done.
Appending file <tautomers.xyz> with structures.

All initial 17 structures from file tautomerize_4.xyz are unique.

===================================================
============= ordered structure list ==============
===================================================
written to file <tautomers.xyz>

structure    ΔE(kcal/mol)   Etot(Eh)
1            0.00        -33.864123
2            2.45        -33.860219
3            3.73        -33.858179
4            3.73        -33.858178
5            8.64        -33.850359
6            9.27        -33.849346
7           10.00        -33.848191
8           10.47        -33.847445
9           10.47        -33.847445
10           16.83        -33.837299
11           19.94        -33.832349
12           20.44        -33.831554
13           22.07        -33.828957
14           25.37        -33.823693
15           26.19        -33.822393
16           27.88        -33.819698
17           28.93        -33.818019

-----------------
Wall Time Summary
-----------------
LMO calc. wall time :         0h : 0m : 0s
multilevel OPT wall time :         0h : 1m :30s
--------------------
Overall wall time  : 0h : 1m :30s

CREST terminated normally.


Tip

The number of protonation/deprotonation cycles can be adjusted with the flag -iter INT, where INT is the number of cycles.

As can be seen from the output, the entire procedure is constructed from the protonation and deprotonation site screening routines. The first protonation step yields the same three protomers that are also obtained by the standalone application, which are then automatically deprotonated. Two protonation/deprotonation cycles are performed. The final tautomer ensemble consists of 17 structures (within 30 kcal/mol) and is written to the file tautomers.xyz.

## Property calculations on final ensemble¶

It is possible to (automatically) perform further calculations on the final conformer ensemble by the usage of the -prop option:

crest [input] [options] -prop [property option]


Currently, there are only a few options available but we plan to implement more.

A useful type of this mode is e.g. the reoptimization of the conformer ensemble with very tight convergence thresholds. In combination with crude conformational search settings such as -quick, -squick or -mquick this helps to ensure the ensemble convergence, i.e., the minimization of artificial structural differences for the same conformer due to too loose geometry optimizations. This reoptimization can be requested by

crest coord -mquick -prop reopt


Updated geometries will generally be written to a new ensemble file called crest_property.xyz.

Another useful runtype of this mode is the calculation of frequencies and reweighting of the conformers on the resulting free energies. E.g.:

crest coord -prop hess


The property mode can also directly be applied to a given ensemble:

crest -forall <ensemble>.xyz -prop [property option]


## Dry run to check settings prior to calculations¶

A dry run can be performed by CREST to verify the settings that would be applied in the calculation. To do this, simply add the -dry flag to the cmd-input line.

crest [input] [options] -dry


With this option nothing will actually be calculated but instead, the settings are printed. E.g. for some random setting:

crest coord -ewin 3.2 -temp 999 -gfn1 -nozs -chrg 1 -cinp .xcontrol.sample -dry

<....>
<....>

******************************************************************************************
**                                  D R Y    R U N                                      **
******************************************************************************************
Dry run was requested.
Running CREST with the chosen cmd arguments will result in the following settings:

Input file : coord

Job type :
1.  Conformational search via the iMTD-GC algo

Job settings
sort Z-matrix        :      F

CRE settings
energy window         (-ewin) :    3.2000
RMSD threshold        (-rthr) :    0.1250
energy threshold      (-ethr) :    0.0500
rot. const. threshold (-bthr) :      0.01
T (for boltz. weight) (-temp) :    999.00

General MD/MTD settings
simulation length [ps]    (-len) : <system dependent>
time step [fs]          (-tstep) :       5.0
shake mode              (-shake) :         2
MTD temperature [K]    (-mdtemp) :    300.00
trj dump step  [fs]    (-mddump) :       100
MTD Vbias dump [ps]    (-vbdump) :       1.0

XTB settings
binary name        (-xnam) : xtb
binary: "xtb"
status: present
path  : /home/thomas/bin/xtb
GFN method         (-gfn)  : --gfn1
(final) opt level  (-opt)  : 2
Molecular charge   (-chrg) : 1

Technical settings
working directory : /tmp1/thomas/


## Examples from the paper: Automated exploration of the low-energy chemical space with fast quantum chemical methods¶

### Conformers of transition-states¶

At first, a transition-state (TS) has to be localized. Then the TS mode has to be identified and reasonable constraints have to be applied to freeze this mode during the CREST run. Choosing suitable constraints is the responsibility of the user.

In this example, a methyl group is transferred onto the catechol molecule. To preserve the TS vibrational mode the atoms which are dominantly contributing to this mode are fixed. In this case, the carbon (36) of the methyl group being transferred, the sulfur (37) of the S-adenosyl- L -methionine (SAM) and the oxygen (35) of the catechol group are constrained. For running the TS conformational search only these atoms have to be constrained. But to retain the surrounding enzyme environment additionally the distances of all ligands to the magnesium cation and the amide magnesium water angle were constrained. As stated before all atoms with constraints have to be removed from the list of atoms which are used in the metadynamics simulation.

crest coord -cinp .constraintinp -g methanol > crest.out

$constrain atoms: 35-37 force constant=0.5 reference=coord.ref distance: 10, 1, auto distance: 2, 1, auto distance: 11, 1, auto distance: 14, 1, auto distance: 9, 1, auto angle: 9, 1, 11, 180$metadyn
atoms: 3-8,12-13,15-34,38-53
$end  $coord
-2.57480197685137   -0.38573933229522    0.86228536590435      Mg
-5.87996595426622   -1.46598597135567   -1.00931632324148      O
-5.79755045954234    1.88737481602186    1.36486580018227      O
-6.93504356011937    0.41703174067196   -0.07677235660280      C
-9.68583177367761    0.93957235453071   -0.70260934507636      C
-9.88785370898918    2.90051382662291   -1.27585066001173      H
-10.31204304615949  -0.31693795001232   -2.19707799857187      H
-10.81224558069477   0.63532604630470    0.98871505743889      H
-1.35732893615725    2.84149984259631    3.74273757259152      O
-1.31788637685368    1.88478932440519   -1.80336662588251      O
-1.03506712269361   -3.09136305475668   -1.65209468828016      O
-3.01034174150676    3.35231258504990    4.30691490291278      H
-0.64007292100150    4.31049584542225    2.93186531615926      H
-3.02042382593105   -2.69109360436689    3.78441246580865      O
-0.67413309122153   -2.78784634989936    4.10013037720282      C
0.80704125300360   -1.59087682326574    2.72475235410942      O
0.37030033373577   -4.45667671167827    6.17913372417457      C
1.65729077111170   -3.36053569450090    7.34278701173010      H
-1.17079464125707   -5.18933342363882    7.31676317209597      H
1.41212360996512   -6.00880794547076    5.32805483610633      H
-0.04610218809699    0.99217247488345   -2.84947633284740      H
-0.58166801572397    4.35407649708453   -2.13719082516246      C
1.69930763718877    4.60968100984284   -3.53188509022323      C
-1.89895861199073    6.41295502711680   -1.26089925937752      C
2.61815567802848    7.04758861150735   -3.94211016089909      C
-0.94293511850593    8.82264113991643   -1.71734825726509      C
-3.65794447068903    6.13213826999732   -0.25859371242962      H
1.29133066638906    9.11831895867148   -3.04019344765619      C
4.35136261809131    7.29515670682662   -4.99253235854911      H
-1.96139641783255   10.45433175989920   -1.03894063047482      H
2.01793975704253   10.99527109251927   -3.38477251662235      H
5.63677744964081   -0.19526366812337   -3.54734464996746      H
3.55857435122244    0.44545364581733   -0.79647639427433      H
6.02794370271953    2.75567866080431   -1.74563412676399      H
2.74773927853638    2.50310064429053   -4.32763740793204      O
5.16232303152189    0.93488296527549   -1.93713143185301      C
7.77908129622702   -0.95480533027442    0.60724611364076      S
6.20470140355368   -3.99408071134196    0.68137239550646      C
7.00770708640275   -5.10883646299712    2.20213746286551      H
4.19551348270129   -3.68373090740626    0.97362752914345      H
6.54643468112530   -4.90904155689111   -1.11917138292065      H
6.61325357496481    0.34737209228094    3.55003016825311      C
7.52593267335208   -0.62757026577676    5.10500275305939      H
7.10342021330197    2.33658535430792    3.58672294810726      H
4.57513571292400    0.10172782556556    3.62256009227771      H
-1.61022171124489   -5.31411191371024   -2.02789529853598      C
-3.17527947979499   -6.57718946281529   -0.51674594958634      N
-3.77763814894346   -8.33207207055257   -0.93763600526181      H
-4.05833804986482   -5.57635320116590    0.85099090510650      H
-0.47266612030322   -6.78426594278943   -4.18601622917577      C
0.51805850799787   -8.43374379675092   -3.46937160488911      H
-1.96305386150678   -7.41025810365247   -5.45278966275112      H
0.83013814067146   -5.58152886274452   -5.21822759129119      H
$end  The TS conformer search yields 141 conformers within 6 kcal/mol. On these conformers, Hessians have to be calculated to ensure that the transition-state mode is preserved. Those conformers with preserved mode can be optimized into the TS and the true TSs have to be confirmed by again a hessian calculation (only one imaginary mode). During the optimization, some conformers can become identical or rotamers of each other. To this end all optimized geometries are appended and sorted with the cregen sorting routine. cat TSconf*.xyz >> allts.xyz crest coord -cregen allts.xyz -ewin 30 > sorting.out  Now after sorting only 91 unique TS conformers are obtained within an energy window of 6.1 kcal/mol. This procedure can in principle be refined at DFT level. ### Conformers of metal-organic systems¶ • trans-Cu(II)(L-valine)2 Calculation of trans-Cu(II)(L-valine)2 conformers in the gas phase. crest coord -nci > crest.out  $coord
-0.002022192318         -0.000684522852          1.349121896005     CU
2.028671941135          2.818125977315          1.174767316951     O
4.406562542342          2.529552834523          0.838287117696     C
5.900488893190          4.242544277537          0.591753944418     O
5.382406579092         -0.254197829091          0.699650595616     C
3.456927714843         -1.958681435237          1.737975874213     N
3.442953703137         -3.661542617496          0.846227450863     H
3.710547158869         -2.249430796311          3.618554595139     H
7.133224715719         -0.349791899055          1.804782999185     H
6.007018333138         -0.877714812490         -2.069473442827     C
7.266213509953         -3.466799912264         -2.312238367182     C
8.881995597301         -3.618089140164         -1.050454618739     H
7.930334466002         -3.738254167109         -4.236839656939     H
5.952357752542         -4.994107920656         -1.890594175637     H
3.663534173447         -0.712885768717         -3.746419767180     C
4.156219468360         -1.164942859389         -5.689573088070     H
2.890265219159          1.189883399588         -3.704912704715     H
2.203522204085         -2.025873622846         -3.126878925482     H
7.355957431563          0.567207315613         -2.680683804317     H
-2.033163868813         -2.819780021566          1.179505209377     O
-4.409877555278         -2.530551975348          0.835068556898     C
-5.903043316660         -4.243023566156          0.580387940800     O
-5.384798675016          0.253509426488          0.697143335052     C
-3.461334991004          1.955672873602          1.742931448447     N
-3.448757571238          3.662158486139          0.858135081470     H
-3.716247763220          2.238184300034          3.624611253622     H
-7.138671974341          0.348502264395          1.797538738740     H
-6.001307995929          0.880859137312         -2.072901114603     C
-7.255902292489          3.472119634743         -2.316426880308     C
-7.917767124579          3.744910887179         -4.241612390481     H
-5.939710712311          4.997073845686         -1.893506102537     H
-8.872648523224          3.626011270865         -1.056195385178     H
-3.653380600330          0.714736239795         -3.743504646086     C
-2.884657484645         -1.189944325855         -3.704494974332     H
-2.192229886598          2.022965931298         -3.116395721134     H
-4.139423979729          1.172691111744         -5.686934420106     H
-7.350580840264         -0.561585906341         -2.689213500551     H
$end   ============================================== | | | C R E S T | | | | Conformer-Rotamer Ensemble Sampling Tool | | based on the GFN methods | | P.Pracht, S.Grimme | | Universitaet Bonn, MCTC | ============================================== Version 2.11, Tue 13. Jul 16:11:14 CEST 2021 Using the xTB program. Compatible with xTB version 6.4.0 <.......> T /K : 298.15 E lowest : -57.69401 ensemble average energy (kcal) : 0.430 ensemble entropy (J/mol K, cal/mol K) : 45.253 10.816 ensemble free energy (kcal/mol) : -3.225 population of lowest in % : 7.134 number of unique conformers for further calc 52 list of relative energies saved as "crest.energies" ----------------- Wall Time Summary ----------------- test MD wall time : 0h : 0m : 5s MTD wall time : 0h :15m :51s multilevel OPT wall time : 0h :49m :17s -------------------- Overall wall time : 1h : 6m :47s CREST terminated normally.  Results in 52 conformers within an energy window of 6 kcal/mol. • [Pt(COMe)2(2-py)3COH] conformers in methanol. crest coord -g methanol -ewin 10 > crest.out  $coord
1.48235976014562      0.32575477023909      0.83983586742930      pt
4.37233116325056     -2.04701937728251      0.66066526359202       c
5.11582123352082     -2.89977152283009     -1.35531347223172       o
5.60331010456907     -2.97886601012202      3.10440618630801       c
5.11582123352082     -1.79782119213888      4.71363082065877       h
4.96457322302306     -4.90914755554552      3.43123243126445       h
7.64542186308448     -3.03767428737742      2.85382472163511       h
3.90413261656682      3.15849014823120      0.32067896584616       c
3.77547628198769      4.50973504009881     -1.55263489557537       o
5.78086877201500      3.82467530185737      2.40255812110202       c
6.44902868945004      5.75938447561023      2.16769917785472       h
4.93481948506077      3.56859662386391      4.26032709535443       h
7.38167845589603      2.54234683232997      2.24297074917982       h
-1.45880054444693     -2.37015120764916      1.99982157738756       n
-1.37380633216814     -3.71993156176379      4.12084829921227       c
-3.47313332880892     -4.91477704969539      5.12088380983082       c
-5.76730431783315     -4.67836853101913      3.87619679514437       c
-5.86160354159028     -3.26072055256804      1.67926544374004       c
-3.65812239940936     -2.14869231241016      0.79621720883004       c
-3.66283159693252     -0.54983471562441     -1.60480456492594       c
-1.36490194262998     -1.28858913220566     -3.20027766220770       c
-1.32606807059918     -3.74293708770554     -3.74494019740640       n
0.45445456851927     -4.60152659727760     -5.28248940926294       c
2.25936790283487     -3.06404352583571     -6.38168829870466       c
2.17878809080250     -0.49502320914006     -5.86813254537940       c
0.32467195716495      0.43733364975533     -4.26146660021256       c
0.14833216307473      2.45190076015779     -3.96574713712955       h
3.52744783732032      0.78490530819858     -6.70693851206628       h
3.68438581320421     -3.84772429150018     -7.60737222739882       h
0.39857914622211     -6.61487483432435     -5.63264243360372       h
-5.86517134452916     -0.98949461824931     -3.04219073283502       o
-5.69660399402350     -2.62769064394335     -3.83817172589844       h
-3.63492223167593      2.20020246734036     -0.78356738209650       c
-1.79344269668899      2.91320936536104      0.78584828153889       n
-1.75920841806563      5.28509912105245      1.61658700736449       c
-3.54797404257573      7.05739011313605      0.91252418313075       c
-5.45207721188036      6.32967358689699     -0.73330822586627       c
-5.50553000527517      3.85501674464698     -1.58299523562631       c
-6.94955289136293      3.18275045232518     -2.84989409127871       h
-6.87435123990475      7.65734792470912     -1.34159783995923       h
-3.43966438926938      8.95769115346132      1.63587922145511       h
-0.24274666012596      5.76489302728759      2.90140613593504       h
-7.59878342212486     -2.99720202278941      0.64743151148342       h
-7.44966324325272     -5.57429713925087      4.59918333687282       h
-3.30863455866736     -5.99888080678762      6.83682316863177       h
0.45096235462570     -3.84321729467325      5.03295296314152       h
$end   ============================================== | | | C R E S T | | | | Conformer-Rotamer Ensemble Sampling Tool | | based on the GFN methods | | P.Pracht, S.Grimme | | Universitaet Bonn, MCTC | ============================================== Version 2.11, Tue 13. Jul 16:11:14 CEST 2021 Using the xTB program. Compatible with xTB version 6.4.0 <.......> T /K : 298.15 E lowest : -78.08070 ensemble average energy (kcal) : 0.551 ensemble entropy (J/mol K, cal/mol K) : 37.238 8.900 ensemble free energy (kcal/mol) : -2.654 population of lowest in % : 43.032 number of unique conformers for further calc 43 list of relative energies saved as "crest.energies" ----------------- Wall Time Summary ----------------- test MD wall time : 0h : 0m :11s MTD wall time : 0h :24m : 9s multilevel OPT wall time : 0h :55m : 9s MD wall time : 0h :13m :46s GC wall time : 0h : 0m :14s -------------------- Overall wall time : 1h :36m :42s CREST terminated normally.  The search for the Pt-complex conformers results in 43 conformers within an energy window of 10 kcal/mol. ### Conformational search of tyrosine on a graphene surface¶ To sample a tyrosine molecule at a graphene surface, the graphene sheet has to be constrained. All atoms in the graphene layer are constrained and removed from the metadynamics list. crest coord -v3 -T 40 -subrmsd -nozs -shake 0 -tstep 1 > crest.out  $constrain
atoms: 1-252
force constant=0.5
reference=coord.input-original
$metadyn atoms: 253-276$end

$coord 25.57030991921202 -1.29059115296523 -0.00598160501741 C 25.57044241258889 1.28341269512943 -0.00397025649369 C 23.26056590790795 2.70217665940709 -0.00029100251731 C 23.24029402398585 5.32779404644931 0.00100734191172 C 20.94157103860908 6.71653777403401 0.00350095166658 C 20.91152361664611 9.36664222799565 0.00390218154564 C 18.62125921494789 10.73533662251798 0.00644642379287 C 18.58134086796354 13.40310199790359 0.00577252431633 C 16.30144187186615 14.75441822463413 0.00911453357094 C 16.24838174294015 17.43954219647988 0.00645557179198 C 13.98481323267349 18.77014376357869 0.00996412506652 C 13.91132086532623 21.47993962309619 0.00398308521361 C 11.68223395792687 22.76705405593083 0.00667868517840 C 23.23975279130400 -5.33474095446540 -0.00731302769541 C 23.26029458648507 -2.70912180306862 -0.00467349937707 C 20.93174016704535 -1.33727196043975 -0.00133108922934 C 20.93188342707722 1.33055529046503 0.00081585427198 C 18.61221093462830 2.68271748197896 0.00282646704916 C 18.60800793365893 5.36022077189572 0.00464910445605 C 16.29058723267624 6.70694827919018 0.00657403025646 C 16.28436011426403 9.38628406493185 0.00875170443409 C 13.96723583506467 10.73158318782874 0.01208246556117 C 13.95992943220878 13.41187709257133 0.01391081920492 C 11.64338138388279 14.75451471117306 0.01811199832376 C 11.63248103339880 17.43948496412882 0.01741770073639 C 9.32215273401024 18.77351998648383 0.02061202665840 C 9.29861569072829 21.47602775444658 0.01579094470882 C 7.01463133268908 22.77127484019967 0.01713945360400 C 20.91057452024432 -9.37335860619177 -0.00926090528278 C 20.94088299656363 -6.72324817926078 -0.00658702044546 C 18.60745075594095 -5.36670680488450 -0.00374295822885 C 18.61193643260484 -2.68920008796749 -0.00153341601501 C 16.28742192884590 -1.34235637938395 -0.00078002692156 C 16.28757499289433 1.33609346344897 0.00147976178734 C 13.96434116375503 2.68237236768262 0.00076404228717 C 13.96287174466134 5.36168711625019 0.00444321914007 C 11.64121337713845 6.70589478724923 0.00506279531532 C 11.63822495880011 9.38856356746231 0.01140806380708 C 9.31876144361668 10.72973740054357 0.01538062834809 C 9.31472052037413 13.41484574971875 0.02046267069700 C 6.99521035114103 14.75419616780989 0.02462006312471 C 6.99130768004798 17.44070137881147 0.02532754092530 C 4.67042012951467 18.77581140475820 0.02736696446206 C 4.66258399962784 21.47489924179938 0.02293852266839 C 2.35249685077769 22.77391798267787 0.02212621551956 C 18.57998109654765 -13.40958568048023 -0.01028264322867 C 18.62015473984217 -10.74181472085148 -0.00815563904508 C 16.28339497432454 -9.39252741923171 -0.00521520823422 C 16.28988963380622 -6.71318737538808 -0.00404056626572 C 13.96230713311354 -5.36770826591533 -0.00442097129394 C 13.96405926362842 -2.68839552363364 -0.00377125200632 C 11.63966160646814 -1.34407984382584 -0.00904818073003 C 11.63980125609782 1.33828860894632 -0.00694514984261 C 9.31718204611965 2.68076977770467 -0.01577395709023 C 9.31651311270946 5.36383477266664 -0.00518866604770 C 6.99345645543046 6.70626536261829 -0.00580602080543 C 6.99238975005242 9.38889650419404 0.01018123529597 C 4.66942445816832 10.73022469984729 0.01596892428477 C 4.66767523754332 13.41536689488851 0.02498093342981 C 2.34659451442003 14.75374729750557 0.02932151339149 C 2.34541319267838 17.44224899252958 0.03052836779358 C 0.02192747834666 18.77650769724976 0.03128547441315 C 0.02204581702233 21.47485010389652 0.02595882570531 C -2.30827777761409 22.77415959011223 0.02256838460730 C 16.24661075554111 -17.44578823181741 -0.01013734215265 C 16.29993060120758 -14.76066846818401 -0.00812704005076 C 13.95855696550417 -13.41788125850394 -0.00444039516866 C 13.96612442985704 -10.73758744438051 -0.00414530231920 C 11.63725550740641 -9.39433325364823 -0.00401359135821 C 11.64051700131476 -6.71165587242432 -0.00602746222362 C 9.31595899918277 -5.36940309841218 -0.01310009453262 C 9.31693993550326 -2.68633606543353 -0.01891241488459 C 6.99250858337540 -1.34364841298911 -0.04053087185396 C 6.99262614528279 1.33843607842166 -0.04039634224145 C 4.66829807447026 2.68060255606494 -0.05849331187865 C 4.66838077810071 5.36444295219266 -0.02946711255395 C 2.34546795808210 6.70546777798594 -0.02011056812930 C 2.34548672067421 9.39005944206936 0.00792927448916 C 0.02151160692621 10.73096229461900 0.01836028425584 C 0.02166355850542 13.41525943333584 0.02919214654642 C -2.30314738868724 14.75399842979222 0.03371873327606 C -2.30170671357899 17.44247566484074 0.03391819200193 C -4.62657873721502 18.77628435247385 0.03298595758151 C -4.61848784408495 21.47537522910175 0.02560169171120 C -6.97041113719043 22.77198785523224 0.01911534529519 C 13.90914113254730 -21.48594598108393 -0.01033584558689 C 13.98290020369888 -18.77616131023010 -0.00756967293109 C 11.63069926259142 -17.44525404116543 -0.00301796684893 C 11.64186594877656 -14.76028958926714 -0.00225240122053 C 9.31334018064636 -13.42037835388799 -0.00050064690806 C 9.31765144447383 -10.73527777129347 -0.00273906743608 C 6.99141240533732 -9.39419601810598 -0.00610150867183 C 6.99273536257410 -6.71153949160536 -0.01572184076338 C 4.66777019559512 -5.36946863827436 -0.03472958133329 C 4.66784980463537 -2.68568430403884 -0.05767595376480 C 2.34451914565195 -1.34413003433670 -0.08972846459708 C 2.34456672574876 1.33936603534043 -0.08992506624553 C 0.02090811162037 2.68094549890774 -0.08525730399650 C 0.02111281557256 5.36367785785738 -0.04218166058112 C -2.30319003521588 6.70557418244421 -0.01593859385830 C -2.30260481415700 9.39011489524983 0.01310861544943 C -4.62640274973063 10.73069866586899 0.02658914458233 C -4.62436575510021 13.41584995240830 0.03462561586354 C -6.95176077190229 14.75491657239231 0.03775667851738 C -6.94759324240958 17.44141219089441 0.03541282761784 C -9.27832130444150 18.77446705578989 0.03155385525560 C -9.25452218190166 21.47696510552652 0.02154959462713 C -11.63802237495646 22.76822838541283 0.01080138060727 C 11.67992598947008 -22.77283570051328 -0.00834317870550 C 9.29642984746100 -21.48156460163871 -0.00342311682088 C 9.32023206578185 -18.77906553363732 -0.00092512411397 C 6.98952062190846 -17.44599854678769 0.00224945815385 C 6.99369455574676 -14.75950793677676 0.00199456075935 C 4.66628544326049 -13.42042472957629 0.00282443615400 C 4.66831941671158 -10.73531049956183 -0.00294605654817 C 2.34450022003777 -9.39484861167554 -0.00889347428569 C 2.34477736575761 -6.71029850254746 -0.03096748479269 C 0.02065664441757 -5.36823814102908 -0.05222779425988 C 0.02061674289975 -2.68553888940278 -0.08961100122795 C -2.30299554292030 -1.34344598487105 -0.09950976794014 C -2.30319722664585 1.33939473396005 -0.09532505353303 C -4.62645210980409 2.68061978914947 -0.05798804837452 C -4.62592518953837 5.36451283149119 -0.02208304225800 C -6.95072782946171 6.70669485989158 0.00967601306812 C -6.94947330532319 9.38953936851952 0.02696512792323 C -9.27574242491885 10.73068901863044 0.03718718622128 C 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# for convergence reasons the md settings were adjusted. # the file .constrains is found automatically

## Preparing a Nanoreactor calculation for xtb¶

This is the current workaround for the nanoreactor procedure described in JCTC, 2019, 15, 2847-2862. Currently, there isn’t an automated procedure for the reactor, but the workarounds can already be used with the crest 2.11 version. The important things here are mainly a definition of metadynamics parameters and the logfermi potential used for external compression of the system. There are 3 steps/commands to it (assuming a given input structure is provided as start.xyz):

1. Generate nano-reactor settings with the command crest start.xyz --reactor --genpot <density> --genmtd <sim.length> which will produce a file called rcontrol containing the correct xtb constraints. <density> can be the required nano-reactor density in g/cm³ like in the JCTC paper, <sim.length> is the metadynamics length in ps. All other settings, e.g. k and α for the metadynamics, must be directly edited in the rcontrol file. This requires some trial and error but the JCTC paper is generally a good guideline, too.

2. Run the metadynamics with the generated settings using xtb simply with the command xtb start.xyz --gfn 2 --md --input rcontrol. The trajectory is saved as xtb.trj.

3. To so some (simple) fragment analyzation of xtb.trj use crest coord --reactor --fragopt. This will extract all fragments from the trajectory based on neighbor lists, optimize their geometry with xtb and sort them.