title: Peptide Bond Isomerization in High-Temperature Simulations.
abstract: Force fields for molecular simulation are generally optimized to model macromolecules such as proteins at ambient temperature and pressure. Nevertheless, elevated temperatures are frequently used to enhance conformational sampling, either during system setup or as a component of an advanced sampling technique such as temperature replica exchange. Because macromolecular force fields are now put upon to simulate temperatures and time scales that greatly exceed their original design specifications, it is appropriate to re-evaluate whether these force fields are up to the task. Here, we quantify the rates of peptide bond isomerization in high-temperature simulations of three octameric peptides and a small fast-folding protein. We show that peptide octamers with and without proline residues undergo cis/trans isomerization every 1-5 ns at 800 K with three classical atomistic force fields (AMBER99SB-ILDN, CHARMM22/CMAP, and OPLS-AA/L). On the low microsecond time scale, these force fields permit isomerization of nonprolyl peptide bonds at temperatures ≥500 K, and the CHARMM22/CMAP force field permits isomerization of prolyl peptide bonds ≥400 K. Moreover, the OPLS-AA/L force field allows chiral inversion about the Cα atom at 800 K. Finally, we show that temperature replica exchange permits cis peptide bonds developed at 540 K to subsequently migrate back to the 300 K ensemble, where cis peptide bonds are present in 2 ± 1% of the population of Trp-cage TC5b, including up to 4% of its folded state. Further work is required to assess the accuracy of cis/trans isomerization in the current generation of protein force fields.
authors: Center for NonLinear Studies (CNLS), MS B258, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, United States.
authors: Chris
authors: C
authors: Neale
authors: Molecular Structure and Function, The Hospital for Sick Children , 686 Bay Street, Toronto, Ontario M5G 0A4, Canada.|Department of Biochemistry, University of Toronto , 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors: Régis
authors: R
authors: Pomès
authors: Center for NonLinear Studies (CNLS), MS B258, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, United States.
authors: Angel E
authors: AE
authors: García
mesh_terms: D000595:Amino Acid Sequence; D006358:Hot Temperature; D007536:Isomerism; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry*; D011392:Proline / Q000737:chemistry; D011487:Protein Conformation; D017510:Protein Folding; D013816:Thermodynamics
chemical_list: D010455:Peptides; D011392:Proline