Improved Modeling of Peptidic Foldamers Using a Quantum Chemical Parametrization Based on Torsional Minimum Energy Path Matching. Issue 7 (4th July 2019)

• Record Type: Journal Article
• Authors: Wacha, András; Beke‐Somfai, Tamás; Nagy, Tibor
• Is Part Of: ChemPlusChem. Volume 84:Issue 7(2019)
• Page Start: 927
• Page End: 941
• Publication Date: 2019-07-04
• Subjects: β-peptides -- foldamers -- force field simulations -- molecular dynamics -- secondary structure; Chemistry -- Periodicals; 540.5
• DOI: 10.1002/cplu.201900180
• Languages: English
• ISSNs: 2192-6506

Abstract

Abstract: The increasing interest in novel foldamer constructs demands an accurate computational treatment on an extensive timescale. However, it is still a challenge to derive a force field (FF) that can reproduce the experimentally known fold while also allowing the spontaneous exploration of other structures. Here, aiming at a realistic reproduction of backbone torsional barriers, the relevant proper dihedrals of acyclic β 2 ‐, β 3 ‐ and β 2, 3 ‐amino acids were added to the CHARMM FF and optimized using a novel, self‐consistent iterative procedure based on quantum chemical relaxed scans. The new FF was validated by molecular dynamics simulations on three acyclic peptides. While they resided most of the time in their preferred fold (>80 % in helices and >50 % in hairpin), they also visited other conformations. Owing to the CHARMM36m‐consistent parametrization, the proposed extension is suitable for exploring new foldamer structures and assemblies, and their interactions with diverse biomolecules. Abstract : [AW1] An extension to the CHARMM36m force field is proposed for the folding of β‐peptides containing β 2 ‐, β 3 ‐ and β 2, 3 ‐amino acids. The parameters of the relevant, weakly correlated backbone dihedral terms were determined by matching the energies along ab initio relaxed torsional paths. This results in a realistic reproduction of folding dynamics even on longer time scales: while the dominant fold is recovered, other conformations are also explored spontaneously.