Exact reaction coordinates for flap opening in HIV-1 protease

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 coor-dinates that can determine the value of committor for any protein configuration, which provide the optimal description of functional dynamics. Despite intensive efforts, iden-tifying the exact reaction coordinates (RCs) in complex molecules remains a formidable challenge. Using the recently developed generalized work functional, we report the discovery of the exact RCs for an important functional process-the flap opening of HIV-1 protease. Our results show that this process has six RCs, each one is a linear combination of similar to 240 backbone dihedrals, providing the precise definition of collectiv-ity and cooperativity in the functional dynamics of a protein. Applying bias potentials along each RC can accelerate flap opening by 10(3) to 10(4) folds. The success in identifying the RCs 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 RCs for its conformational changes are known. Our results suggest that the generalized work functional (GWF) might be the fundamental operator of mechanics that controls protein dynamics.

Automated summary

The primary goal of protein science is to understand the functional mechanisms of proteins and their transitions between different functional structures. However, identifying the exact reaction coordinates in complex molecules remains challenging. In this study, the researchers used a generalized work functional to discover the exact reaction coordinates for the flap opening of HIV-1 protease, providing a precise definition of collectivity and cooperativity in protein dynamics.