Nanosecond Molecular Dynamics of HIV Protease-Inhibitor Complexes:Insights Into the Differential Binding Potency of Diastereoisomeres


M. Lepšík1, Z. Kříž2 and Z. Havlas1


1Department of Theoretical Chemistry and Centre for Complex Molecular Systems and Biomolecules, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Praha, Czech Republic


2National Centre for Biomolecular Research (NCBR), Faculty of Science, Masaryk University, Kotlářská 2, Czech Republic, Brno, Czech Republic



            The inhibitory potency of four nanomolar diastereomeric inhibitors of HIV-1 protease [1] was studied by molecular dynamics simulations and MM-GBSA/PBSA analysis. As a starting point we used the crystal structures of protease-inhibitor complexes [2, 3]. Having added hydrogens, we surrounded the complexes with a box of explicit water molecules and added counterions to neutralize the box.  Using AMBER 7 program package [4], we minimized, heated and equilibrated the system after which we ran 2-nanosecond-long production dynamics. Periodic boundary conditions were used and long-range electrostatics was treated by particle mesh Ewald (PME) technique.


            An analysis of the molecular dynamical trajectories was performed and their quality assessed. The protease-inhibitor binding energies were calculated with MM-GBSA/PBSA approach. The effect of the length of the simulation, method to calculate solvation energy, and other factors upon the results was determined.



[1] Konvalinka J, Litera J, Weber J, Vondrášek J, Hradílek M, Soucek M, Pichová I, Majer P, Štrop P, Sedlácek J, Heuser AM, Kottler H. and Kraeusslich HG, Eur. J. Biochem. 250, (1997), 559-566

[2] J Weber, JR Mesters, M Lepšík, J Prejdová, M Švec, J Šponarová, P Mlčochová, K Stříšovský, T Uhlíková, M Souček, L Machala, M Staňková, J Vondrášek, T Klimkait, HG Kraeusslich, R Hilgenfeld & J Konvalinka, J Mol Biol, 324, (2002), 739-54, pdb code 1IZH

[3] Mesters et al, unpublished data

[4] D.A.Case, D.A. Pearlman, J.W. Caldwell, T.E. Cheatham III, J. Wang, W.S. Ross, C.L. Simmerling, T.A. Darden, K.M. Merz, R.V. Stanton, A.L. Cheng, J.J. Vincent, M.Crowley, V. Tsui, H. Gohlke, R.J. Radmer, Y. Duan, J. Pitera, I. Massova, G.L. Seibel, U.C. Singh, P.K. Weiner & P.A. Kollman (2002), AMBER 7, University of California, San Francisco



We owe thanks for financial help to the Ministry of Education (MŠMT) of the Czech Republic (project LN 00A032) and also are grateful for support to Dr. Jiří Vondrášek and the Grant Agency of the Czech Republic (grant number 203/00/0828).