Folding free energy landscapes of ß-sheets with non-polarizable and polarizable CHARMM force fields.

Molecular dynamics (MD) simulations of peptides and proteins offer atomic-level detail into many biological processes, although the degree of insight depends on the accuracy of the force fields used to represent them. Protein folding is a key example in which the accurate reproduction of folded-state conformations of proteins and kinetics of the folding processes in simulation is a longstanding goal. Although there have been a number of recent successes, challenges remain in capturing the full complexity of folding for even secondary-structure elements. In the present work, we have used all-atom MD simulations to study the folding properties of one such element, the C-terminal ß-hairpin of the B1 domain of streptococcal protein G (GB1). Using replica-exchange umbrella sampling simulations, we examined the folding free energy of two fixed-charge CHARMM force fields, CHARMM36 and CHARMM22*, as well as a polarizable force field, the CHARMM Drude-2013 model, which has previously been shown to improve the folding properties of α-helical peptides. The CHARMM22* and Drude-2013 models are in rough agreement with experimental studies of GB1 folding, while CHARMM36 overstabilizes the ß-hairpin. Additional free-energy calculations show that small adjustments to the atomic polarizabilities in the Drude-2013 model can improve both the backbone solubility and folding properties of GB1 without significantly affecting the model's ability to properly fold α-helices. We also identify a non-native salt bridge in the ß-turn region that overstabilizes the ß-hairpin in the C36 model. Finally, we demonstrate that tryptophan fluorescence is insufficient for capturing the full ß-hairpin folding pathway.

Evaluating the London Dispersion Coefficients of Protein Force Fields Using the Exchange-Hole Dipole Moment Model.

London dispersion is one of the fundamental interactions involved in protein folding and dynamics. The popular CHARMM36, Amber ff14sb, and OPLS-AA force fields represent these interactions through the C6/ r6 term of the Lennard-Jones potential, where the C6 parameters are assigned empirically. Here, dispersion coefficients of these three force fields are shown to be roughly 50% larger than values calculated using the quantum mechanically derived exchange-hole dipole moment (XDM) model. The CHARMM36 and Amber OL15 force fields for nucleic acids also exhibit this trend. The hydration energies of the side-chain models were calculated using REMD-TI for the CHARMM36, Amber ff14sb, and OPLS-AA force fields. These force fields predict side-chain hydration energies that are in generally good agreement with the experimental values, which suggests that the total strength of aqueous dispersion interactions is correct, despite C6 coefficients that are considerably larger than XDM predicts. An analytical expression for the dispersion hydration energy using XDM coefficients shows that higher-order dispersion terms (i.e., C8 and C10) account for roughly 37.5% of the hydration energy of methane. This suggests that the C6 dispersion coefficients used in contemporary force fields are elevated to account for the neglected higher-order terms.