Comparative Study of Molecular Mechanics Force Fields for β-Peptidic Foldamers: Folding and Self-Association

J Chem Inf Model. 2023 Jun 26;63(12):3799-3813. doi: 10.1021/acs.jcim.3c00175. Epub 2023 Jun 6.

Abstract

Computer-assisted study and design of non-natural peptidomimetics is increasingly important in the development of novel constructs with widespread applicability. Among these methods, molecular dynamics can accurately describe monomeric as well as oligomeric states of these compounds. We studied seven different sequences composed of cyclic and acyclic β-amino acids, the closest homologues of natural peptides, and compared the performance on them of three force field families in which specific modifications were made to improve reproduction of β-peptide structures. Altogether 17 systems were simulated, each for 500 ns, testing multiple starting conformations and in three cases also oligomer formation and stability from eight β-peptide monomers. The results indicated that our recently developed CHARMM force field extension, based on torsional energy path matching of the β-peptide backbone against quantum-chemical calculations, performs best overall, reproducing the experimental structures accurately in all monomeric simulations and correctly describing all the oligomeric examples. The Amber and GROMOS force fields could only treat some of the seven peptides (four in each case) without further parametrization. Amber was able to reproduce the experimental secondary structure of those β-peptides which contained cyclic β-amino acids, while the GROMOS force field had the lowest performance in this sense. From the latter two, Amber was able to hold together already formed associates in the prepared state but was not able to yield spontaneous oligomer formation in the simulations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amber*
  • Amino Acids
  • Humans
  • Molecular Dynamics Simulation*
  • Peptides / chemistry
  • Protein Structure, Secondary

Substances

  • Amber
  • Peptides
  • Amino Acids