Biophys J, August 2002, p. 794-807, Vol. 83, No. 2

Molecular Dynamics Simulations of the First Steps of the Reaction Catalyzed by HIV-1 Protease

Joanna Trylska,^* Piotr Baa,^* Maciej Geller,^* and Pawe Grochowski^*

 ^*Interdisciplinary Centre for Mathematical and Computational Modelling, Warsaw University, 02-106 Warsaw, Poland;  Faculty of Mathematics and Computer Science, N. Copernicus University, 87-100 Toru, Poland; and  Department of Biophysics, Warsaw University, 02-089 Warsaw, Poland

The mechanism of the first steps of the reaction catalyzed by HIV-1 protease was studied through molecular dynamics simulations. The potential energy surface in the active site was generated using the approximate valence bond method. The approximate valence bond (AVB) method was parameterized based on density functional calculations. The surrounding protein and explicit water environment was modeled with conventional, classical force field. The calculations were performed based on HIV-1 protease complexed with the MVT-101 inhibitor that was modified to a model substrate. The protonation state of the catalytic aspartates was determined theoretically. Possible reaction mechanisms involving the lytic water molecule are accounted for in this study. The modeled steps include the dissociation of the lytic water molecule and proton transfer onto Asp-125, the nucleophilic attack followed by a proton transfer onto peptide nitrogen. The simulations show that in the active site most preferable energetically are structures consisting of ionized or polarized molecular fragments that are not accounted for in conventional molecular dynamics. The mobility of the lytic water molecule, the dynamics of the hydrogen bond network, and the conformation of the aspartates in the active center were analyzed.

Biophys J, August 2002, p. 794-807, Vol. 83, No. 2
© 2002 by the Biophysical Society   0006-3495/02/08/794/14  $2.00

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