doi:10.1016/j.cplett.2005.07.075 
Copyright © 2005 Elsevier B.V. All rights reserved.
A coarse grained model for the dynamics of flap opening in HIV-1 protease
Valentina Tozzinia, b, 
, 
and J. Andrew McCammonc
aNEST – Scuola Normale Superiore, Piazza dei Cavalieri, 7 I-56126 Pisa, Italy
bDepartment of Chemistry and Biochemistry and Center for Theoretical Biological Physics, University of California, San Diego, La Jolla, CA 92093, USA
cHoward Hughes Medical Institute and Department of Chemistry and Biochemistry, Department of Pharmacology and Center for Theoretical Biological Physics, University of California, San Diego, La Jolla, CA 92093, USA
Received 13 April 2005;
revised 12 July 2005.
Available online 10 August 2005.
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Abstract
A coarse grained model for proteins is developed and applied to HIV-1 protease. Molecular dynamics simulations on the μsec timescale and the use of a flexible force field allow study of the opening of the ‘flaps’ protecting the active site. The opening mechanism reveals peculiar features that might be involved in the substrate capture. An allosteric inhibition effect is demonstrated in specific regions of the protein. This study indicates alternative conformations and target sites to be used as basis for the design of novel inhibitor drugs.
Fig. 1. Upper left part: HIV-1 protease structure, full atom and secondary structure representation. Upper right part: coarse grained model. The two symmetrical subunits (res 1–99 and 100–198) are represented in blue and red. The flaps (res 43–57) are in yellow, and other relevant regions (active site (res 24–27, a), flap tip (res 49–52, b), 39-turn and 17-turn (38–40, c and 16–18, d) are in green. In the lower part, the coarse graining is schematically represented.
Fig. 2. Boltzmann inversion and parameterization for the bond angle potential. Bond angle probability distribution (a) and its Boltzmann inverse (b). (c) Quartic (green) and harmonic potentials (blue and red). Arrows indicate the scale for each plot.
Fig. 3. (a–d) The flap tip distance as a function of time in the following different simulations: (a) 
10 μs simulation; (b) the same after integrating out the shorter opening events; (c) a simulation with the allosteric constraint; (d) a simulation with the ‘single well’ harmonic potential; (e, f) The closing (toff) and opening (ton) interval distributions during the simulation of (a).
Fig. 4. Structures: flap opening (a, b) and switching (c). Main plot: flap tip distance as a function of time. Insets on the left: distribution of the flap tip distances; inset on the right: distributions of the curling angle. Solid lines are the distributions for the open structures, dotted lines for the closed structures. Inset on the right: distribution of open ton (solid line) and closed toff (dotted line) time intervals.
Fig. 5. Correlation plot between the projection onto the first and onto the seventh principal modes. Fitting lines are reported. The modes patterns are represented near the axes.
Abstract
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