Calculation of absolute free energy of binding for theophylline and its analogs to RNA aptamer using nonequilibrium work values

Details Calculation of absolute free energy of binding for theophylline and its analogs to RNA aptamer using nonequilibrium work values Calculation of absolute free energy of binding for theophylline and its analogs to RNA aptamer using nonequilibrium work values

2007-08-06

arxiv.org/abs/0708.0698v1

Physics

Condensed Matter

Soft Condensed Matter

23 pages including 6 figures

Scientific paper

10.1016/j.chemphys.2007.07.014

The massively parallel computation of absolute binding free energy with a well-equilibrated system (MP-CAFEE) has been developed [H. Fujitani, Y. Tanida, M. Ito, G. Jayachandran, C. D. Snow, M. R. Shirts, E. J. Sorin, and V. S. Pande, J. Chem. Phys. ${\bf 123}$, 084108 (2005)]. As an application, we perform the binding affinity calculations of six theophylline-related ligands with RNA aptamer. Basically, our method is applicable when using many compute nodes to accelerate simulations, thus a parallel computing system is also developed. To further reduce the computational cost, the adequate non-uniform intervals of coupling constant $\lambda$, connecting two equilibrium states, namely bound and unbound, are determined. The absolute binding energies $\Delta G$ thus obtained have effective linear relation between the computed and experimental values. If the results of two other different methods are compared, thermodynamic integration (TI) and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) by the paper of Gouda $et al$ [H. Gouda, I. D. Kuntz, D. A. Case, and P. A. Kollman, Biopolymers ${\bf 68}$, 16 (2003)], the predictive accuracy of the relative values $\Delta\Delta G$ is almost comparable to that of TI: the correlation coefficients (R) obtained are 0.99 (this work), 0.97 (TI), and 0.78 (MM-PBSA). On absolute binding energies meanwhile, a constant energy shift of $\sim$ -7 kcal/mol against the experimental values is evident. To solve this problem, several presumable reasons are investigated.

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