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.
References:
[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[3] Mesters et al, unpublished data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
Acknowledgements:
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).