Complete reconstruction of an enzyme-inhibitor binding process by molecular dynamics simulations

被引:513
作者
Buch, Ignasi [1 ]
Giorgino, Toni [1 ]
De Fabritiis, Gianni [1 ]
机构
[1] Univ Pompeu Fabra, Computat Biochem & Biophys Lab, Barcelona 08003, Spain
关键词
binding affinity; distributed computing; Markov state model; transition-state kinetics; association rates; FREE-ENERGY; STATE MODELS; THIOFLAVIN-T; DRUG-ACTION; TIME-SCALE; TRYPSIN; MECHANISM; FORCE; PROTEINS; KINETICS;
D O I
10.1073/pnas.1103547108
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The understanding of protein-ligand binding is of critical importance for biomedical research, yet the process itself has been very difficult to study because of its intrinsically dynamic character. Here, we have been able to quantitatively reconstruct the complete binding process of the enzyme-inhibitor complex trypsin-benzamidine by performing 495 molecular dynamics simulations of free ligand binding of 100 ns each, 187 of which produced binding events with an rmsd less than 2 angstrom compared to the crystal structure. The binding paths obtained are able to capture the kinetic pathway of the inhibitor diffusing from solvent (S0) to the bound (S4) state passing through two metastable intermediate states S2 and S3. Rather than directly entering the binding pocket the inhibitor appears to roll on the surface of the protein in its transition between S3 and the final binding pocket, whereas the transition between S2 and the bound pose requires rediffusion to S3. An estimation of the standard free energy of binding gives Delta G degrees = -5.2 +/- 0.4 kcal/mol (cf. the experimental value -6.2 kcal/mol), and a two-states kinetic model k(on) = (1.5 +/- 0.2) x 10(8) M(-1) s(-1) and k(off) = (9.5 +/- 3.3) x 10(4) s(-1) for unbound to bound transitions. The ability to reconstruct by simple diffusion the binding pathway of an enzyme-inhibitor binding process demonstrates the predictive power of unconventional high-throughput molecular simulations. Moreover, the methodology is directly applicable to other molecular systems and thus of general interest in biomedical and pharmaceutical research.
引用
收藏
页码:10184 / 10189
页数:6
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