Exact reaction coordinates for flap opening in HIV-1 protease

Area of Science:

• Computational Biology
• Protein Dynamics
• Biophysics

Background:

• Understanding protein function necessitates comprehending the dynamic transitions between functional structures.
• Identifying exact reaction coordinates (RCs) is crucial for describing protein functional dynamics but remains challenging for complex molecules.

Purpose of the Study:

• To discover the exact reaction coordinates (RCs) for the flap opening process in HIV-1 protease.
• To demonstrate the utility of the generalized work functional (GWF) in identifying RCs for complex proteins.

Main Methods:

• Utilized the recently developed generalized work functional (GWF) to identify RCs.
• Analyzed the flap opening process of HIV-1 protease, a protein with 198 residues.

Main Results:

• Identified six exact RCs for HIV-1 protease flap opening, each a linear combination of approximately 240 backbone dihedrals.
• Demonstrated that applying bias potentials along these RCs accelerates flap opening by several orders of magnitude.
• This represents significant progress beyond the alanine dipeptide, the only other complex molecule with known exact RCs.

Conclusions:

• The generalized work functional (GWF) is a powerful tool for discovering exact RCs in complex proteins.
• The identified RCs provide a precise definition of collectivity and cooperativity in protein functional dynamics.
• The GWF may represent a fundamental operator controlling protein mechanical dynamics.