Macrocycle Conformational Sampling by DFT-D3/COSMO-RS Methodology
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F18%3A00489512" target="_blank" >RIV/61388963:_____/18:00489512 - isvavai.cz</a>
Result on the web
<a href="http://dx.doi.org/10.1021/acs.jcim.7b00453" target="_blank" >http://dx.doi.org/10.1021/acs.jcim.7b00453</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acs.jcim.7b00453" target="_blank" >10.1021/acs.jcim.7b00453</a>
Alternative languages
Result language
angličtina
Original language name
Macrocycle Conformational Sampling by DFT-D3/COSMO-RS Methodology
Original language description
To find and calibrate a robust and reliable computational protocol for mapping conformational space of medium-sized molecules, exhaustive conformational sampling has been carried out for a series of seven macrocyclic compounds of varying ring size and one acyclic analogue. While five of them were taken from the MD/LLMOD/force field study by Shelley and co-workers (Watts, K. S., Dalai, P., Tebben, A. J., Cheney, D. L., Shelley, J. C. Macrocycle Conformational Sampling with MacroModel. J. Chem. Inf. Model. 2014, 54, 2680-2696), three represent potential macrocyclic inhibitors of human cyclophilin A. The free energy values (GDFT/cosmo-Rs) for all of the conformers of each compound were obtained by a composite protocol based on in vacuo quantum mechanics (DFT-D3 method in a large basis set), standard gas-phase thermodynamics, and the COSMO-RS solvation model. The G(DFT/COSMO-RS) values were used as the reference for evaluating the performance of conformational sampling algorithms: standard and extended MD/LLMOD search (simulated-annealing molecular dynamics with low-lying eigenvector following algorithms, employing the OPLS2005 force field plus GBSA solvation) available in MacroModel and plain molecular dynamics (MD) sampling at high temperature (1000 K) using the semiempirical quantum mechanics (SQM) potential SQM(PM6-D3H4/COSMO) followed by energy minimization of the snapshots. It has been shown that the former protocol (MD/LLMOD) may provide a more complete set of initial structures that ultimately leads to the identification of a greater number of low-energy conformers (as assessed by GDFT/COSMO-RS) than the latter (i.e., plain SQM MD). The CPU time needed to fully evaluate one medium-sized compound (similar to 100 atoms, typically resulting in several hundred or a few thousand conformers generated and treated quantum-mechanically) is approximately 1,000-100,000 CPU hours on today's computers, which transforms to 1-7 days on a small-sized computer cluster with a few hundred CPUs. Finally, our data sets based on the rigorous quantum-chemical approach allow us to formulate a composite conformational sampling protocol with multiple checkpoints and truncation of redundant structural data that offers superior insights at affordable computational cost.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10403 - Physical chemistry
Result continuities
Project
<a href="/en/project/GA17-24155S" target="_blank" >GA17-24155S: Exploring Conformational Space of Short Peptides by Advanced Quantum Chemical and Solvation Methods: A Key to Understand Protein Structures?</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2018
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Journal of Chemical Information and Modeling
ISSN
1549-9596
e-ISSN
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Volume of the periodical
58
Issue of the periodical within the volume
1
Country of publishing house
US - UNITED STATES
Number of pages
13
Pages from-to
48-60
UT code for WoS article
000423255500006
EID of the result in the Scopus database
2-s2.0-85040922403