Comparison and Evaluation of Force Fields for Intrinsically Disordered Proteins

Abstract

Molecular dynamics (MD) simulations of six upgraded empirical force fields were compared and evaluated with short peptides, intrinsically disordered proteins, and folded proteins using trajectories of 1, 1.5, 5, or 10 μs (five replicates of 200 ns, 300 ns, 1 μs, or 2 μs) for each system. Previous studies have shown that different force fields, water models, simulation methods, and parameters can affect simulation outcomes. Here, the MD simulations were done in an explicit solvent with RS-peptide, HEWL19, HIV-rev, β amyloid (Aβ)-40, Aβ-42, phosphodiesteraseγ, CspTm, and ubiquitin using ff 99IDPs, ff14IDPs, ff14IDPSFF, ff03w, CHARMM36m, and CHARMM22* force fields. The IDP ensembles generated by six all-atom empirical force fields were compared against NMR data. Despite using identical starting structures and simulation parameters, ensembles obtained with different force fields exhibit significant differences in NMR RMDs, secondary structure contents, and global properties such as the radius of gyration. The intrinsically disordered protein (IDP)-specific force fields could substantially reproduce the experimental observables in force field comparison: they have the lowest error in chemical shifts and J-couplings for short peptides/proteins, reasonably well for large IDPs and reasonably well with the radius of gyration. A high population of disorderness was observed in the IDP-specific force field for the IDP ensemble with a fraction of β sheets for β-amyloids. CHARMM22* performs better for many observables; however, it still has a preference toward the helicity for short peptides. The results of β-amyloid 42 starting from two different initial structures (Aβ42 1Z0Q and Aβ42 model ) were also compared with DSSP and NMR data. The results obtained with IDP-specific force fields within 2 μs simulation time are similar, even though starting from different structures. The current force fields perform equally well for folded proteins. The results of currently developed or modified force fields for IDPs are capable of enlightening the overall performance of the force field for disordered as well as folded proteins, thereby contributing to force field development.

Secondary structure dependence of amyloid‐β(1–40) on simulation techniques and force field parameters

“…Despite, our REMD simulations result in slightly different helical abundancies for residues than the simulations conducted by Rahman et al. (2020) using the ff99IDPs and ff14IDPS parameters. Finally, we looked at the sequence‐based secondary structure propensity of Aβ 1‐40 using one of the most accurate methods for secondary structure prediction Jpred4.…”

Aggregation and Its Influence on the Bioactivities of a Novel Antimicrobial Peptide, Temporin-PF, and Its Analogues

“…The initial monomolecular simulation for each peptide was conducted in a water box for 100 ns with a modified water model, TIP4P-D, and Amber99SB-ILDN forcefield. They can substantially reproduce the experimental observables for intrinsically disordered proteins and peptides [ 37 , 38 ]. The energy analysis demonstrated that each peptide monomer system was stable and validated, as seen in Supplementary Figure S5 .…”

A kinetic ensemble of the Alzheimer’s Aβ peptide

“…Cloud architectures, such as the Google Compute Engine, are especially well suited to generate Markov state models, as the individual simulations can be run independently from one another, with no communication between machines required 35 . We chose the CHARMM22* over the CHARMM36m force field due to the better agreement with macroscopic observables such as radius of gyration for the closely related Aβ40 peptide 36,37 .…”