The primary goal of protein science is to understand how proteins function, which requires understanding the functional dynamics responsible for transitions between different functional structures of a protein. A central concept is the exact reaction coordinates that can determine the value of committor for any protein configuration, which provide optimal characterization of functional dynamics. Despite intensive efforts, identifying exact reaction coordinates in complex molecules remains a formidable challenge. Using the recently developed generalized work functional, we report the discovery of the exact reaction coordinates for an important functional process--the flap opening of HIV-1 protease. Our results show that this process has six reaction coordinates, each one is a linear combination of ~240 backbone dihedrals, providing exact definition of collectivity and cooperativity in functional dynamics of proteins. Applying bias potential along each reaction coordinate can accelerate flap opening by 10<sup>3</sup> to 10<sup>4 </sup>folds. The success in identifying the reaction coordinates of a protein with 198 residues represents a significant progress beyond that of the alanine dipeptide, currently the only other complex molecule for which the exact reaction coordinates for its conformational changes are known. Our results suggest that the generalized work functional might be the fundamental mechanical operator that controls protein dynamics.

Exact reaction coordinates for functional protein dynamics: Flap opening in HIV-1 protease

Where thousands of chemistry professionals meet to share ideas and advance scientific and technical knowledge. Spring 2023 abstracts, posters, and presentations will launch at the end of March.

ACS Spring 2023

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.