The accurate prediction of drug binding affinities is an ongoing goal within drug optimisation and development. Current binding free energy methods use forcefields to calculate interaction energies, which due to their empirical nature and the neglect of electrons, cannot usually describe polarisation or account for electron transfer. This can limit the accuracy with which interactions are calculated and consequently free energy calculations. In an attempt to overcome these limitations within the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) method, the linear-scaling DFT program, ONETEP[1], is used to calculate the interaction energies, using a  minimum parameter implicit solvent approach within the self-consistent calculation[2]. We present a preliminary application of this �QM-PBSA�[3,4] method on a number of small aromatic ligands bound in the polar cavity of the T4-lysozyme mutant L99A/M102Q[5], including extensive testing of the solvation model. Our DFT calculations are performed with a near-complete basis set on more than 2600 atoms.   [1] C.-K. Skylaris, P. D. Haynes, A. A. Mostofi and M. C. Payne, J. Chem. Phys. 122  , 084119 (2005).[2] J. Dziedzic, H. H. Helal, C.-K. Skylaris, A. A. Mostofi and M. C. Payne, Europhysics Letters 95  , 43001 (2011)[3] D. J. Cole, C.-K. Skylaris, E. Rajendra, A. R. Venkitaraman and M. C. Payne. Europhysics Letters  91,  37004 (2010)[4] S. Fox, H. Wallnoefer, T. Fox, C. Tautermann and C.-K. Skylaris. J. Chem. Theor. Comput., 7  , 1102 (2011).[5] B. Q. Wei, W. A. Baase, L. H. Weaver, B. W. Matthews and B. K. Shoichet, J. Mol. Biol. 322  , 339     (2002).

Near-complete basis set DFT calculations on entire proteins: Application to free energies of binding in T4 lysozyme L99A/M102Q

243rd National Meeting (2012)

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