Coarse-Grained Modeling of the HIV–1 Protease Binding Mechanisms: I. Targeting Structural Flexibility of the Protease Flaps and Implications for Drug Design

  • Gennady M. Verkhivker
Part of the Lecture Notes in Computer Science book series (LNCS, volume 5488)


We propose a coarse–grained model to study binding mechanism of the HIV–1 protease inhibitors using long equilibrium simulations with an ensemble of the HIV–1 protease crystal structures. A microscopic analysis suggests a binding mechanism, in which the HIV–1 protease drugs may exploit the dynamic equilibrium between thermodynamically stable, high affinity complexes with the closed form of the HIV–1 protease and meta–stable intermediate complexes with the alternative structural forms of the protease. We have found that formation of the hydrophobic interaction clusters with the conserved flap residues may stabilize semi–open and open forms of the enzyme and lead to weakly bound, transient inhibitor complexes. The results suggest that inhibitors may function through a multi-mechanistic effect of stabilizing structurally different conformational states of the protease, highlighting the molecular basis of the flap residues in developing drug resistance.


Protein flexibility Monte Carlo simulations protease flaps binding mechanism drug design 


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Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Gennady M. Verkhivker
    • 1
    • 2
  1. 1.Department of Pharmaceutical Chemistry, School of Pharmacy and Center for BioinformaticsThe University of KansasLawrenceUSA
  2. 2.Department of PharmacologyUniversity of California San DiegoLa JollaUSA

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