Sampling of the conformational landscape of small proteins with Monte Carlo methods

Sci Rep. 2020 Oct 23;10(1):18211. doi: 10.1038/s41598-020-75239-7.

Abstract

Computer simulation provides an increasingly realistic picture of large-scale conformational change of proteins, but investigations remain fundamentally constrained by the femtosecond timestep of molecular dynamics simulations. For this reason, many biologically interesting questions cannot be addressed using accessible state-of-the-art computational resources. Here, we report the development of an all-atom Monte Carlo approach that permits the modelling of the large-scale conformational change of proteins using standard off-the-shelf computational hardware and standard all-atom force fields. We demonstrate extensive thermodynamic characterization of the folding process of the α-helical Trp-cage, the Villin headpiece and the β-sheet WW-domain. We fully characterize the free energy landscape, transition states, energy barriers between different states, and the per-residue stability of individual amino acids over a wide temperature range. We demonstrate that a state-of-the-art intramolecular force field can be combined with an implicit solvent model to obtain a high quality of the folded structures and also discuss limitations that still remain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computer Simulation
  • Hydrogen Bonding
  • Models, Chemical
  • Molecular Dynamics Simulation
  • Monte Carlo Method
  • Protein Conformation*
  • Protein Folding
  • Proteins / chemistry*
  • Thermodynamics

Substances

  • Proteins