Enzymes
are protein molecules which catalyze important chemical reactions in
our body. To perform their action, enzymes bind to other molecules
called ligands or substrates. Sometimes, enzymes must be blocked to
prevent them to cause diseases, like in the case of HIV-1 protease
which is involved in AIDS. A small ligand (drug) is therefore designed
which binds to the enzyme blocking it. Often the mechanism by which the
drug binds to the enzyme is not known.   Binding mechanism of HIV-1 protease We investigated the mechanism by which a small peptide substrate binds to HIV-1 protease. To this aim, we performed long molecular dynamics simulations (1.6 microsec) using an accurate explicit solvent force field, and accelerating the exploration of 7 reaction coordinates by bias-exchange metadynamics. We observed several times the ligand approaching the enzyme and binding to it. The structure of the complex is in excellent agreement with the crystallographic evidences. From the simulation we constructed a kinetic model describing the stability of the intermediate states and the rates of interconversion among them. The computed binding free energy and association/dissociation rates are in agreement with available experiments.  It turns out that opening of the protease flaps is not required for the binding process, and that expulsion of the water molecules from the enzyme cavity is a key kinetic step. We hope that the insight we obtained on the binding pathway will help the rational design of more effective drugs. Our present research effort is devoted to make this type of binding calculations easy to use and accessible to all users of molecular dynamics programs. Pietrucci, Marinelli, Carloni, and Laio, J Am Chem Soc 2009, 131(33): 11811 Marinelli, Pietrucci, Laio, and Piana, PLoS Comput Biol 2009, 5(8): e1000452 |
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