Examining the Stability of β-Sheets using the Charmm Drude Polarizable Force Field

Abstract

β-Sheets are some of the most common secondary structure motifs in proteins, and are important for mediating protein-protein interactions through their association. This association can also lead to the aggregation of misfolded proteins into β-pleated-sheets in neurodegenerative disorders like Alzheimer's disease. Fixed charge, all-atom molecular dynamics simulations have adequately reproduced the folding free energy landscape of a small β-hairpin, the GB1 domain of protein G, which is a prototype for a larger β-pleated-sheet. Polarizable force fields should, in theory, be able to more accurately reproduce experimental results as they are a more realistic model of the molecular system. The CHARMM Drude model is a relatively efficient polarizable force field that has been shown to perform as well or better than traditional non-polarizable force fields in reproducing helical content and folding mechanisms of model α-helical peptides. To assess the model's accuracy for β-sheets, we examined the stability of the GB1 β-hairpin using the CHARMM Drude polarizable force field and two non-polarizable force fields, CHARMM36 and CHARMM22∗. Two-dimensional replica exchange umbrella sampling (REUS) simulations show that the β-hairpin is unstable in the Drude system, whereas it is either stable or quasistable in CHARMM36 and CHARMM22∗, respectively. The instability in Drude appears to be driven mostly by interactions between the peptide backbone and the surrounding water molecules. By tuning these interactions, we have shiftedthe stability back towards the β-hairpin state.