Abstract
Molecular dynamics simulations are an invaluable tool to characterize the dynamic motions of proteins in atomistic detail. However, the accuracy of models derived from simulations inevitably relies on the quality of the underlying force field. Here, we present an evaluation of current non-polarizable and polarizable force fields (AMBER ff14SB, CHARMM 36m, GROMOS 54A7, and Drude 2013) based on the long-standing biophysical challenge of protein folding. We quantify the thermodynamics and kinetics of the β-hairpin formation using Markov state models of the fast-folding mini-protein CLN025. Furthermore, we study the (partial) folding dynamics of two more complex systems, a villin headpiece variant and a WW domain. Surprisingly, the polarizable force field in our set, Drude 2013, consistently leads to destabilization of the native state, regardless of the secondary structure element present. All non-polarizable force fields, on the other hand, stably characterize the native state ensembles in most cases even when starting from a partially unfolded conformation. Focusing on CLN025, we find that the conformational space captured with AMBER ff14SB and CHARMM 36m is comparable, but the ensembles from CHARMM 36m simulations are clearly shifted toward disordered conformations. While the AMBER ff14SB ensemble overstabilizes the native fold, CHARMM 36m and GROMOS 54A7 ensembles both agree remarkably well with experimental state populations. In addition, GROMOS 54A7 also reproduces experimental folding times most accurately. Our results further indicate an over-stabilization of helical structures with AMBER ff14SB. Nevertheless, the presented investigations strongly imply that reliable (un)folding dynamics of small proteins can be captured in feasible computational time with current additive force fields.
Highlights
The physiological function and physico-chemical properties of biomolecules are inherently linked to their conformational ensembles.1–3 Computational techniques, ranging from structure refinement tools4–6 to simulations of protein motions,7–9 are indispensable for the study of thermodynamics, kinetics, and mechanisms encoded within conformational ensembles.10 In particular, in the field of biomolecular simulations, they have repeatedly proven to be of great value for understanding and predicting macromolecular quantities based on fundamental interaction potentials.11,12The study of how proteins fold into their functional threedimensional structure, i.e., their native state, is a prominent example in this respect
Focusing on CLN025, we find that the conformational space captured with AMBER ff14SB and CHARMM 36m is comparable, but the ensembles from CHARMM 36m simulations are clearly shifted toward disordered conformations
We provide a survey of protein folding and unfolding dynamics in three non-polarizable force fields, i.e., AMBER ff14SB,38 CHARMM 36m,39 and GROMOS 54A7,40,41 and the polarizable Drude 2013 force field
Summary
The physiological function and physico-chemical properties of biomolecules are inherently linked to their conformational ensembles. Computational techniques, ranging from structure refinement tools to simulations of protein motions, are indispensable for the study of thermodynamics, kinetics, and mechanisms encoded within conformational ensembles. In particular, in the field of biomolecular simulations, they have repeatedly proven to be of great value for understanding and predicting macromolecular quantities based on fundamental interaction potentials.11,12The study of how proteins fold into their functional threedimensional structure, i.e., their native state, is a prominent example in this respect. Based on the idea that the native state is thermodynamically stable at physiological conditions and on the fact that a random search of the conformational space is incompatible with the experimentally observed folding times, the concept of folding funnels emerged.. Based on the idea that the native state is thermodynamically stable at physiological conditions and on the fact that a random search of the conformational space is incompatible with the experimentally observed folding times, the concept of folding funnels emerged.15,16 Following this concept, the native state represents the most favorable minimum in a protein’s free energy landscape (FEL). The native state, for example, is not one static structure but characterized by constant conformational rearrangements.19 These motions are small and fast compared to transitions to the unfolded scitation.org/journal/jcp conformational ensemble. When we refer to the native state, we really discuss the native state ensemble
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