Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 25, Pages 10184-10189Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1103547108
Keywords
binding affinity; distributed computing; Markov state model; transition-state kinetics; association rates
Categories
Funding
- Fundacio La Marato de TV3
- Beatriu de Pinos programme of the Generalitat de Catalunya
- Virtual Physiological Human Network of Excellence
- Ramon y Cajal scheme
- Spanish Ministry of Science and Innovation [FIS2008-01040]
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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.
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