Critical Comparison of Biomembrane Force Fields: Protein–Lipid Interactions at the Membrane Interface

Abstract

Molecular dynamics (MD) simulations offer the possibility to study biological processes at high spatial and temporal resolution often not reachable by experiments. Corresponding biomolecular force field parameters have been developed for a wide variety of molecules ranging from inorganic ligands and small organic molecules over proteins and lipids to nucleic acids. Force fields have typically been parametrized and validated on thermodynamic observables and structural characteristics of individual compounds, e.g. of soluble proteins or lipid bilayers. Less strictly, due to the added complexity and missing experimental data to compare to, force fields have hardly been tested on the properties of mixed systems, e.g. on protein-lipid systems. Their selection and combination for mixed systems is further complicated by the partially differing parametrization strategies. Additionally, the presence of other compounds in the system may shift the subtle balance of force field parameters. Here, we assessed the protein-lipid interactions as described in the four atomistic force fields GROMOS54a7, CHARMM36 and the two force field combinations Amber14sb/Slipids and Amber14sb/Lipid14. Four observables were compared, focusing on the membrane-water interface: the conservation of the secondary structure of transmembrane proteins, the positioning of transmembrane peptides relative to the lipid bilayer, the insertion depth of side chains of unfolded peptides absorbed at the membrane interface, and the ability to reproduce experimental insertion energies of Wimley-White peptides at the membrane interface. Significant differences between the force fields were observed that affect e.g. membrane insertion depths and tilting of transmembrane peptides.

Massively Parallel Implementation of Steered Molecular Dynamics in Tinker-HP: Comparisons of Polarizable and Non-Polarizable Simulations of Realistic Systems

“…Large number of benchmark studies have been already performed to compare force fields for proteins and lipids. [45][46][47][48][49][50][51][52][53][54] In most cases, discrepancies could be observed between the simulations and the experimental data.…”

Influence of Transmembrane Helix Mutations on Cytochrome P450-Membrane Interactions and Function

“…Sampling of the configurational space of CYP-membrane systems is challenging and, for this purpose, we have chosen to combine running longer CG replicas, for which convergence can be more readily monitored both within and between replicas, with shorter AA replicas starting from representative coordinates generated in CG simulations. Encouragingly, a recent critical comparison of force fields for simulating diverse proteinmembrane systems showed rather good performance for protein-lipid interactions at the membrane interface for the atomic detail AMBER ff14sb/LIPID 14 force field combination that we have used in this work (52). Moreover, the similarity of the CYP-membrane arrangements from our CG and AA simulations as well as the agreement with experimental observations suggests that our simulations can be used to examine the dependence of CYP positioning in the membrane on protein sequence.…”

The importance of the membrane interface as the reference state for membrane protein stability

“…In principle, full-peptide insertion values could be obtained via potential of mean force (PMF) partitioning calculations, as previously shown for both atomistic [16, 17] and coarse grained representations [18, 19]. However, we and others have shown that such simulations involve enormous convergence challenges [20, 21], which are related to the strong bilayer perturbation caused by the transition between surface and transmembrane state.…”