The Role of Force Fields and Water Models in Protein Folding and Unfolding Dynamics

Abstract

Protein folding is a fascinating, not fully understood phenomenon in biology. Molecular dynamics (MD) simulations are an invaluable tool to study conformational changes in atomistic detail, including folding and unfolding processes of proteins. However, the accuracy of the conformational ensembles derived from MD simulations inevitably relies on the quality of the underlying force field in combination with the respective water model. Here, we investigate protein folding, unfolding, and misfolding of fast-folding proteins by examining different force fields with their recommended water models, i.e., ff14SB with the TIP3P model and ff19SB with the OPC model. To this end, we generated long conventional MD simulations highlighting the perks and pitfalls of these setups. Using Markov state models, we defined kinetically independent conformational substates and emphasized their distinct characteristics, as well as their corresponding state probabilities. Surprisingly, we found substantial differences in thermodynamics and kinetics of protein folding, depending on the combination of the protein force field and water model, originating primarily from the different water models. These results emphasize the importance of carefully choosing the force field and the respective water model as they determine the accuracy of the observed dynamics of folding events. Thus, the findings support the hypothesis that the water model is at least equally important as the force field and hence needs to be considered in future studies investigating protein dynamics and folding in all areas of biophysics.

Partition analysis of dipole moments in solution applied to functional groups in polypeptide motifs

“…Protein folding 88,89 is a transformation from an extended form to a native conformation, during which α-helices 90–92 and β-turns may be formed in some parts of a protein, and the analysis of dipole moments of polypeptide motifs may be used for understanding protein folding. In many biochemical systems, helices play an important role, for example, in G-protein coupled receptors (GPCR), 78,93 which may be analyzed with the method developed in this work.…”

Simulation-Driven Design of Stabilized SARS-CoV-2 Spike S2 Immunogens

“…16) for alchemical non-equilibrium free energy calculations, two independent systems representing the unfolded and folded states of the protein were generated. To approximate the unfolded state, considering the limitations of empirical force fields in simulating unfolded proteins [89][90][91] and given the unavailability of the S2 trimer unfolded structure, we used a capped tripeptide (G-X-G) built with Chimera, 92 where X is the amino acid of interest (either V, T, or W). We note that this approach has been commonly adopted in alchemical free energy calculations and has proven to align well with experimental data.…”