Mapping Conformational Space of All 8000 Tripeptides by Quantum Chemical Methods: What Strain Is Affordable within Folded Protein Chains?

0542023 - ÚOCHB 2022 RIV US eng J - Journal Article
Culka, Martin - Kalvoda, Tadeáš - Gutten, Ondrej - Rulíšek, Lubomír
Mapping Conformational Space of All 8000 Tripeptides by Quantum Chemical Methods: What Strain Is Affordable within Folded Protein Chains?
Journal of Physical Chemistry B. Roč. 125, č. 1 (2021), s. 58-69. ISSN 1520-6106. E-ISSN 1520-5207
R&D Projects: GA ČR(CZ) GA20-08772S
Institutional support: RVO:61388963
Keywords : protein structure * quantum chemistry * energy
OECD category: Physical chemistry
Impact factor: 3.466, year: 2021
Method of publishing: Limited access
https://doi.org/10.1021/acs.jpcb.0c09251

To gain more insight into the physicochemical aspects of a protein structure from the first principles, conformational space of all 8000 “capped” tripeptides (i.e., N-Ac-X1X2X3-NH-CH3, where Xi is one of the 20 natural amino acids) was investigated computationally. An enormous dataset (denoted P-CONF_1.6M and containing close to 1 600 000 conformers in total) has been obtained by employing a composite protocol combining density functional theory, semiempirical quantum mechanics (SQM), and state-of-the-art solvation methods with 1000 K molecular dynamics (MD) used to generate initial structures (200 snapshots for each tripeptide). This allowed us to present the first rigorous QM-based glimpse at the vast conformational space spanned by small protein fragments. The same computational procedure was repeated for tripeptide fragments taken from the SCOPe database of three-dimensional protein folds, by restraining them to their geometry in a protein. Such complementary data allowed us to compare the distribution of conformational strain energies of unrestrained tripeptidic fragments “in solvent” with those in existing protein chains. Besides providing a rigorous (ab initio) proof of a few well-known concepts and hypotheses concerning protein structures, such as the distribution of (φ, ψ) angles in Ramachandran plots, we have made several observations that came as a certain surprise: (1) distribution of conformational energies does not significantly differ between the “unbiased/unrestrained” conformers obtained from MD sampling in solvent and the biased conformers, i.e., those of a given tripeptide obtained from protein structures, (2) conformational (strain) energy window up to ∼20 to 25 kcal·mol–1 is readily available to tripeptide fragments within the context of a protein chain, (3) overpopulation in certain regions of Ramachandran plot was observed for the unbiased conformers. Last but not least, the massive dataset of accurate (DFT-D3//COSMO-RS) conformational (free) energies of ∼1.6 M peptide conformers, P-CONF_1.6M, obtained throughout this work may serve as excellent dataset for calibrating and benchmarking of popular force fields.
Permanent Link: http://hdl.handle.net/11104/0319519


Research data: OSF