Monte Carlo Free Ligand Diffusion with Markov State Model Analysis and Absolute Binding Free Energy Calculations

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• 作者：Ryoji Takahashi ; Víctor A. Gil ; Victor Guallar
• 刊名：Journal of Chemical Theory and Computation
• 出版年：2014
• 出版时间：January 14, 2014
• 年：2014
• 卷：10
• 期：1
• 页码：282-288
• 全文大小：436K
• ISSN：1549-9626

文摘

Obtaining absolute binding free energies from unbiased ligand diffusion has attracted a significant amount of attention due to its implications in drug design. Several studies have used special purpose computers and software to achieve microsecond molecular dynamics which, combined with a Markov state model analysis, are capable of providing absolute binding free energies. We have recently developed a Monte Carlo based technique, PELE, capable of performing a dynamical exploration of the protein鈥搇igand energy landscape including free ligand diffusion into the active site, at a fraction of the computational cost of molecular dynamics techniques. We demonstrate here the capabilities of our Monte Carlo technique in obtaining absolute binding free energies for a series of benzamidine like inhibitors into trypsin. Our results are in good agreement with experimental data and other molecular dynamics simulations, indicating that PELE can be a useful tool for quick estimates of binding free energies and mechanisms.