A Computational Study of The Villin Headpiece Subdomain HP36: The Effect of Hydration on Side Chain Dynamics in the Hydrophobic Core

Hydrophobic side-chain interactions are considered the major dynamic force in the folding of globular proteins and aggregation of non-globular proteins. Due to its small size, a villin headpiece subdomain HP36 is an ideal system to compute the influence of hydrophobic side-chain interaction on protein stability. Alzheimer’s has been attributed to the interactions between the hydrophobic side chains, such as phenylalanine, to drive beta-amyloid (AB) aggregation. Molecular modeling is used to gain insight into how protein-protein interactions and flexibility of the hydrophobic core are altered with the hydration level of HP36. The calculated free energy profiles will be used to estimate the rate constant for ring flipping and determine the effects of relative solvation on transition frequencies, lifetimes, and populations of the residues. These results can have implications on the hydrophobic residue interactions that drives the aggregation of AB plaques in patients with Alzheimer’s.