A critical assessment of force field accuracy against NMR data for cyclic peptides containing β-amino acids

Abstract

Hybrid cyclic α/β-peptides, in which one or more β-amino acids are incorporated into the backbone, are gaining increasing interest as potential therapeutics, thanks to their ability to achieve enhanced binding affinities for a biological target through pre-organization in solution. The in silico prediction of their three dimensional structure through strategies such as MD simulations would substantially advance the rational design process. However, whether the molecular mechanics force fields are accurate in sampling highly constrained cyclopeptides containing β-amino acids remains to be verified. Here, we present a systematic assessment of the ability of 8 widely used force fields to reproduce 79 NMR observables (including chemical shifts and 3J scalar couplings) on five cyclic α/β-peptides that contain the integrin recognition motif isoDGR. Most of the investigated force fields, which include force fields from AMBER, OPLS, CHARMM and GROMOS families, display very good agreement with experimental 3J(HN,Hα), suggesting that MD simulations could be an appropriate tool in the rational design of therapeutic cyclic α-peptides. However, for NMR observables directly related to β-amino acids, we observed a poor agreement with experiments and a remarkable dependence of our evaluation on the choice of Karplus parameters. The force field weaknesses herein unveiled might constitute a source of inspiration for further force field optimization.

Applications of Molecular Dynamics Simulation in Structure Prediction of Peptides and Proteins

“…Recently, simulation of guanylin (a 15-residue peptide with four cysteines) showed that the distribution of three disulfide-bond isomers is in qualitative agreement with experiment, but the most stable conformation of the isomer 2 is significantly different from the poorly ordered structure of the truncated peptide [110]. In another study, BE-META simulations were performed on five cyclic isoDGR-containing α/β-peptides using eight widely used force fields with explicit water to reproduce 79 NMR observables [111]. Most of the force fields display good agreement with experimental 3 J (HN,Hα) , but poor agreement was observed for NMR observables directly related to β-amino acids.…”

Elucidating Solution Structures of Cyclic Peptides Using Molecular Dynamics Simulations

“…Because the force fields most commonly used for peptide simulations were not parametrized for β-amino acids such as iso D, their utility for in silico structure prediction of these compounds remains to be determined. In a recent work, Paissoni et al evaluated the performance of eight force fields in simulating five cyclic peptides containing the iso DGR motif . The eight force fields tested were: AMBER-99SB, AMBER-99SB-ILDN, AMBER-99SB*, AMBER-14SB, OPLS-AA/L, OPLS-AA/L STD , CHARMM-27, and GROMOS-54a7 .…”

“…In a recent work, Paissoni et al evaluated the performance of eight force fields in simulating five cyclic peptides containing the iso DGR motif . The eight force fields tested were: AMBER-99SB, AMBER-99SB-ILDN, AMBER-99SB*, AMBER-14SB, OPLS-AA/L, OPLS-AA/L STD , CHARMM-27, and GROMOS-54a7 . The five benchmark cyclic peptides included two disulfide-bonded pentapeptides: C iso DGRC and Ace-C iso DGRC, and two head-to-tail cyclized hexapeptides: cyclo-(CG iso DGRG), cyclo-(GC iso DGRG), and cyclo-(Cphg iso DGRG), where phg denotes phenylglycine (Figure ).…”

Glycan-induced protein dynamics in human norovirus P dimers depend on virus strain and deamidation status

“…All MD simulations were performed using Gromacs on the Rackham cluster of the Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX), and the Kebnekaise cluster at the High Performance Computing Center North (HPC2N) [37]. The amber99sb force field was utilized for all simulations [38], modified to include parameters for iD and F [39]. The MkVsites tool provided virtual sites and dummy-mass constructions for F [40].…”