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N-H⋯X interactions stabilize intra-residue C5 hydrogen bonded conformations in heterocyclic α-amino acid derivatives.

ABSTRACT: Nature makes extensive and elaborate use of hydrogen bonding to assemble and stabilize biomolecular structures. The shapes of peptides and proteins rely significantly on N-H⋯O[double bond, length as m-dash]C interactions, which are the linchpins of turns, sheets and helices. The C5 H-bond, in which a single residue provides both donor and acceptor, is generally considered too weak to force the backbone to adopt extended structures. Exploiting the synergy between gas phase (experimental and quantum chemistry) and solution spectroscopies to decipher IR spectroscopic data, this work demonstrates that the extended C5-based conformation in 4-membered ring heterocyclic α-amino acid derivatives is significantly stabilized by the formation of an N-H⋯X H-bond. In this synergic system the strength of the C5 interaction remains constant while the N-H⋯X H-bond strength, and thereby the support provided by it, varies with the heteroatom.

SUBMITTER: Mundlapati VR

PROVIDER: S-EPMC8597926 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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N-H⋯X interactions stabilize intra-residue C5 hydrogen bonded conformations in heterocyclic α-amino acid derivatives.

Mundlapati Venkateswara Rao VR Imani Zeynab Z D'mello Viola C VC Brenner Valérie V Gloaguen Eric E Baltaze Jean-Pierre JP Robin Sylvie S Mons Michel M Aitken David J DJ

Chemical science 20211022 44

Nature makes extensive and elaborate use of hydrogen bonding to assemble and stabilize biomolecular structures. The shapes of peptides and proteins rely significantly on N-H⋯O[double bond, length as m-dash]C interactions, which are the linchpins of turns, sheets and helices. The C5 H-bond, in which a single residue provides both donor and acceptor, is generally considered too weak to force the backbone to adopt extended structures. Exploiting the synergy between gas phase (experimental and quant ...[more]

PMID: 34820098

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Project description:The protein docking problem has two major aspects: sampling conformations and orientations, and scoring them for fit. To investigate the extent to which the protein docking problem may be attributed to the sampling of ligand side-chain conformations, multiple conformations of multiple residues were calculated for the uncomplexed (unbound) structures of protein ligands. These ligand conformations were docked into both the complexed (bound) and unbound conformations of the cognate receptors, and their energies were evaluated using an atomistic potential function. The following questions were considered: (1) does the ensemble of precalculated ligand conformations contain a structure similar to the bound form of the ligand? (2) Can the large number of conformations that are calculated be efficiently docked into the receptors? (3) Can near-native complexes be distinguished from non-native complexes? Results from seven test systems suggest that the precalculated ensembles do include side-chain conformations similar to those adopted in the experimental complexes. By assuming additivity among the side chains, the ensemble can be docked in less than 12 h on a desktop computer. These multiconformer dockings produce near-native complexes and also non-native complexes. When docked against the bound conformations of the receptors, the near-native complexes of the unbound ligand were always distinguishable from the non-native complexes. When docked against the unbound conformations of the receptors, the near-native dockings could usually, but not always, be distinguished from the non-native complexes. In every case, docking the unbound ligands with flexible side chains led to better energies and a better distinction between near-native and non-native fits. An extension of this algorithm allowed for docking multiple residue substitutions (mutants) in addition to multiple conformations. The rankings of the docked mutant proteins correlated with experimental binding affinities. These results suggest that sampling multiple residue conformations and residue substitutions of the unbound ligand contributes to, but does not fully provide, a solution to the protein docking problem. Conformational sampling allows a classical atomistic scoring function to be used; such a function may contribute to better selectivity between near-native and non-native complexes. Allowing for receptor flexibility may further extend these results.

Dataset Information

N-H⋯X interactions stabilize intra-residue C5 hydrogen bonded conformations in heterocyclic α-amino acid derivatives.

Publications

N-H⋯X interactions stabilize intra-residue C5 hydrogen bonded conformations in heterocyclic α-amino acid derivatives.

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