Consensus modes, a robust description of protein collective motions from multiple-minima normal mode analysis--application to the HIV-1 protease.
Protein flexibility is essential for enzymatic function, ligand binding, and protein-protein or protein-nucleic acid interactions. Normal mode analysis has increasingly been shown to be well suited for studying such flexibility, as it can be used to identify favorable structural deformations that correspond to functional motions. However, normal modes are strictly relevant to a single structure, reflecting a particular minimum on a complex energy surface, and are thus susceptible to artifacts. We describe a new theoretical framework for determining "consensus" normal modes from a set of related structures, such as those issuing from a short molecular dynamics simulation. This approach is more robust than standard normal mode analysis, and provides higher collectivity and symmetry properties. In an application to HIV-1 protease, the low-frequency consensus modes describe biologically relevant motions including flap opening and closing that can be used in interpreting structural changes accompanying the binding of widely differing inhibitors.
Batista
Paulo Ricardo
PR
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, Brasil.
Robert
Charles Herbert
CH
Maréchal
Jean-Didier
JD
Hamida-Rebaï
Meriam Ben
MB
Pascutti
Pedro Geraldo
PG
Bisch
Paulo Mascarello
PM
Perahia
David
D
D016333:HIV Protease / Q000737:chemistry*; D015497:HIV-1; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation
D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1