Book of Abstracts: Albany 2011
June 14-18 2011
©Adenine Press (2010)
Reconstructing an enzyme-inhibitor binding process by molecular dynamics simulations
The understanding of protein-ligand binding is of critical importance for biomedical research, yet the process itself has been very difficult to study due to its intrinsically dynamic character. In this talk, we will go through the quantitative reconstruction of the complete binding process of the enzyme-inhibitor complex Trypsin-Benzamidine performed with molecular dynamics simulations of free inhibitor binding. The binding events obtained are able to capture the kinetic pathway of the inhibitor diffusing from solvent to bound passing for few metastable intermediate states. Unexpectedly, rather than directly entering the binding pocket, the inhibitor appears to roll on the surface of the protein to the final binding pocket. The trajectories are analysed via a Markov state model-based analysis which additionally yields the kinetic parameters and binding affinity of the interaction. These results show an impressive predictive power for unconventional high-throughput molecular simulations. At the same time, the general methodology is easily applicable to other molecular systems becoming of interest to biomedical and pharmaceutical research.
Gianni De Fabritiis
Research Group of biomedical Informatics (GRIB-IMIM)