Communication: Multiple atomistic force fields in a single enhanced sampling simulation

Abstract

The main concerns of biomolecular dynamics simulations are the convergence of the conformational sampling and the dependence of the results on the force fields. While the first issue can be addressed by employing enhanced sampling techniques such as simulated tempering or replica exchange molecular dynamics, repeating these simulations with different force fields is very time consuming. Here, we propose an automatic method that includes different force fields into a single advanced sampling simulation. Conformational sampling using three all-atom force fields is enhanced by simulated tempering and by formulating the weight parameters of the simulated tempering method in terms of the energy fluctuations, the system is able to perform random walk in both temperature and force field spaces. The method is first demonstrated on a 1D system and then validated by the folding of the 10-residue chignolin peptide in explicit water.

Structures of the Alzheimer’s Wild-Type Aβ1-40 Dimer from Atomistic Simulations

“…As Aβ1-40 peptide is much less prone to aggregation than the more toxic Aβ1-42 peptide, our predictions can be more readily verified by experimental means. Using the CHARMM22* force field that cannot fit normal mode frequencies with high accuracy , but reproduces well the structural properties of many peptides, ,, the Aβ1-40 dimer at 315 K is highly disordered with a very large number of structures differing in secondary structure composition and tertiary and quaternary contacts. However, it is possible to identify transient configurations with β-hairpin structures that persist from the monomer ,, to dimer simulations, are consistent with in vitro experiments of oligomers, and may act as seeds for polymerization into parallel or antiparallel β-sheets.…”

Atazanavir, Alone or in Combination with Ritonavir, Inhibits SARS-CoV-2 Replication and Proinflammatory Cytokine Production

“…Since the tertiary structure (3D) of the SARS-CoV-2 Mpro is a homodimer, we focused the molecular dynamics on only one chain, chain A. Molecular dynamics calculations were performed using NAMD 2.9 ( 49 ) and Charmm27* force field ( 50 ) at pH 7, i.e., with deprotonated Glu and Asp, protonated Arg and Lys, and neutral His with a protonated Nε atom. This all-atom force field has been able to fold properly many soluble proteins ( 51 – 53 ). The soluble proteins were centered in a cubic box of transferable intermolecular potential with 3 points (TIP3P) water molecules ( 54 ); the box extended 1.2 nm outside the protein on its four lateral sides, and the appropriate numbers of Na + and Cl − ions were added to ensure system neutralization.…”