Unfolding of the Villin Headpiece Domain: Revealing Structural Heterogeneity with Time-Resolved X-Ray Solution Scattering and Markov State Modeling.

ABSTRACT: Understanding protein folding pathways is crucial to deciphering the principles of protein structure and function. Here, the unfolding dynamics of the 35-residue villin headpiece (HP35) and a norleucine-substituted variant (2F4K) using a combination of experimental and computational techniques is investigated. Time-resolved X-ray solution scattering coupled with equilibrium molecular dynamics simulations and Markov state modeling reveals distinct unfolding mechanisms between the two variants: HP35 and 2F4K. Specifically, HP35 exhibits a two-state unfolding process, whereas an intermediate state is identified for the 2F4K mutant. A Markov state model constructed from simulations is used to map atomic-level transitions to experimental observations, providing insights into the role of sequenc

SUBMITTER: Nijhawan AK 

PROVIDER: S-EPMC12188166 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature