Abstract
The binding of a set of 10 triphenoxypyridine derivatives to two serine proteases, factor Xa and trypsin, has been used to analyze factors related to sampling and convergence in free energy calculations based on molecular dynamics simulation techniques. The inhibitors investigated were initially proposed as part of the Critical Assessment of Techniques for Free Energy Evaluation (CATFEE) project for which no experimental results nor any assessment of the predictions submitted by various groups have ever been published. The inhibitors studied represent a severe challenge for explicit free energy calculations. The mutations from one compound to another involve up to 19 atoms, the creation and annihilation of net charge and several alternate binding modes. Nevertheless, we demonstrate that it is possible to obtain highly converged results (± 5–10 kJ/mol) even for such complex multi-atom mutations by simulating on a nanosecond time scale. This is achieved by using soft-core potentials to facilitate the creation and deletion of atoms and by a careful choice of mutation pathway. The results show that given modest computational resources, explicit free energy calculations can be successfully applied to realistic problems in drug design.
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van Gunsteren, W.F. and Berendsen, H. J.C., Angew. Chem. Int. Ed. Engl., 29 (1990) 992.
Kollman, P.A., Chem. Rev., 93, (1993) 2395.
Mark, A.E., van Helden, S.P., Smith, P.E., Janssen, L. H.M. and van Gunsteren, W.F., J. Am. Chem. Soc., 116 (1994) 6293.
Mark, A.E., Free energy perturbation calculations. In Encyclopedia of Computational Chemistry, van RagueSchleyer, P., editor, Vol. 2, 1070-1083. John Wiley & Sons (1998).
Dixit, S.B. and Chipot, C., J. Phys. Chem. A, 105 (2001) 9795.
van Gunsteren, W.F., Daura, X. and Mark, A.E., Helvetica Chimica Acta, 85 (2002) 3113.
Chipot, C. and Pearlman, D.A. Mol. Sim., 28 (2002) 1.
Radmer, R.J. and Kollman, P.A., J. Comput. Aided Mol. Des., 12 (1998) 215.
Essex, J.W., Severance, D.L., Tirado-Rives, J. and Jorgensen, W.L., J. Phys. Chem. B, 101 (1997) 9663.
Blas, J.R., Marquez, M., Sessier, J.L., Luque, F.J. and Orozco, M., J. Am. Chem. Soc., 124 (2002) 12796.
Adler, M., Davey, D.D., Phillips, G.B., Kim, S.H., Jancarik, J., Rumennik, G., Light, D.R. and Whitlow, M., Biochemistry, 39 (2000) 12534.
Whitlow, M., Arnaiz, D.O., Buckman, B.O., Davey, D.D., Griedel, B., Guilford, W.J., Koovakkat, S.K., Liang, A., Mohan, R., Phillips, G.B., Seto, M., haw, K. J.S., Xu, W., Zhao, Z., Light, D.R. and Morrissey, M.M., Act. Cryst. D., D55 (1999) 1395.
van Gunsteren, W.F., Billeter, S.R., Eising, A.A., Hünenberger, P.H., Krüger, P., Mark, A.E., Scott, W. R.P. and Tironi, I.G. Biomolecular Simulation: GROMOS96 Manual and User Guide. BIOMOS b.v., Zürich, Groningen, 1996.
Schuler, L.D. and van Gunsteren, W.F., Mol. Sim., 25 (2000) 301.
Frisch, M.J., Trucks, G.W., Schlegel, H.B., Gill, P. M.W., Johnson, B.G., Robb, M.A., Cheeseman, J.R., Keith, T.A., Petersson, G.A., Montgomery, J.A., Raghavachari, K., Al-Laham, M.A., Zakrzewski, V.G., Ortiz, J.V., Foresman, J.B., Ciosloswki, J., Stefanof, B.B., Nanayakkara, A., Challacombe, M., Peng, C.Y., Ayala, P.Y., Chen, W., Wong, M.W., Andres, J.L., Replogle, E.S., Gomperts, R., Martin, R.L., Fox, D.J., Binkley, J.S., Defrees, D.J., Baker, J., Stewart, J.P., Head-Gordon, M., Gonzalez, C. and Pople, J.A., Gaussian 94, Revision A.1. Gaussian, Inc., Pittsburgh PA, 1995.
Besler, B.H., Merz Jr. K.M. and Kollman, P.A., J. Comp. Chem., 11 (1990) 431.
Berendsen, H. J.C., van der Spoel, D. and van Drunen, R., Comp. Phys. Comm., 91 (1995) 43.
Lindahl, E., Hess, B. and van der Spoel, D., J. Mol. Model., 7 (2001) 306.
van der Spoel, D., van Buuren, A.R., Apol, E., Meulenhoff, P.J., Tieleman, D.P., Sijbers, A.L.T.M., Hess, B., Feenstra, K.A., Lindahl, E., van Drunen, R. and Berendsen, H.J.C., Gromacs User Manual version 3.0. Nijenborgh 4, 9747 AG Groningen, The Netherlands. Internet: http://www.gromacs.org, (2001).
Berendsen, H.J.C., Postma, J. P.M., van Gunsteren, W.F., and Hermans, J., Interaction models for water in relation to protein hydration. In Intermolecular Forces, Pullman, B. Ed.) D. Reidel Publishing Company, Dordrecht, 1981, 331-342.
Berendsen, H.J.C., Postma, J.P.M., van Gunsteren, W.F., DiNola, A., and Haak, J.R., J. Chem. Phys., 81 (1984) 3684.
Miyamoto, S. and Kollman, P.A., J. Comp. Chem., 13 (1992) 952.
Hess, B., Bekker, H., Berendsen, H.J.C. and Fraaije, J.G.E.M., J. Comp. Chem., 18 (1997) 1463.
Kirkwood, J.G., J. Chem. Phys., 3 (1935) 300.
Beutler, T.C., Mark, A.E., van Schaik, R.C., Geber, P.R. and van Gunsteren, W.F., Chem. Phys. Lett., 222 (1994) 529.
Liu, H., Mark, A.E. and van Gunsteren, W.F., J. Phys. Chem., 100 (1996) 9485.
Schaefer, H., Gunsteren, W. F.V. and Mark, A.E., J. Comp. Chem., 20 (1999) 1604.
Pitera, J.W. and Gunsteren, W.F.V., J. Phys. Chem. B, 105 (2001) 11264.
Villa, A. and Mark, A.E., J. Comp. Chem., 23 (2002) 548.
Bishop, M. and Frinks, S., J. Chem. Phys., 87 (1987) 3675.
Allen, M.P. and Tildesley, D.J., Computer Simulations of Liquids. Oxford Science Publications, Oxford, 1987.
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Villa, A., Zangi, R., Pieffet, G. et al. Sampling and convergence in free energy calculations of protein-ligand interactions: The binding of triphenoxypyridine derivatives to factor Xa and trypsin. J Comput Aided Mol Des 17, 673–686 (2003). https://doi.org/10.1023/B:JCAM.0000017374.53591.32
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DOI: https://doi.org/10.1023/B:JCAM.0000017374.53591.32