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

被引:12
作者
Tanida, Yoshiaki [1 ]
Ito, Masakatsu [1 ]
Fujitani, Hideaki [1 ]
机构
[1] Fujitsu Labs Ltd, Kanagawa, Japan
关键词
absolute free energy calculation; nonequilibrium work theorem; molecular simulation; theophylline; RNA;
D O I
10.1016/j.chemphys.2007.07.014
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
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, MR. Shirts, E.J. Sorin, V.S. Pande, J. Chem. Phys. 123 (2005) 084108]. 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, P.A. Kollman, Biopolymers 68 (2003) 16], 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 similar to-7 kcal/mol against the experimental values is evident. To solve this problem, several presumable reasons are investigated. (c) 2007 Elsevier B.V. All rights reserved.
引用
收藏
页码:135 / 143
页数:9
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