Improving the Efficiency of Protein鈥揕igand Binding Free-Energy Calculations by System Truncation

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• 作者：Samuel Genheden ; Ulf Ryde
• 刊名：Journal of Chemical Theory and Computation
• 出版年：2012
• 出版时间：April 10, 2012
• 年：2012
• 卷：8
• 期：4
• 页码：1449-1458
• 全文大小：311K
• 年卷期：v.8,no.4(April 10, 2012)
• ISSN：1549-9626

文摘

We have studied whether the efficiency of alchemical free-energy calculations with the Bennett acceptance ratio method of protein鈥搇igand binding energies can be improved by simulating only part of the protein. To this end, we solvated the full protein in a spherical droplet with a radius of 46 脜, surrounded by a vacuum. Then, we systematically reduced the size of the droplet and at the same time ignored protein residues that were outside the droplet. Radii of 40鈥?5 脜 were tested. Ten inhibitors of the blood clotting factor Xa were studied, and the results were compared to an earlier study in which the protein was solvated in a periodic box, showing complete agreement between the two sets of calculations within statistical uncertainty. We then show that the simulated system can be truncated down to 15 脜, without changing the calculated affinities by more than 0.5 kJ/mol on average (maximum difference of 1.4 kJ/mol). Moreover, we show that reducing the number of intermediate states in the calculations from eleven to three gave deviations that, on average, were only 0.5 kJ/mol (maximum of 1.4 kJ/mol). Together, these results show that truncation is an appropriate way to improve the efficiency of free-energy calculations for small mutations that preserve the net charge of the ligand. In fact, each calculation of a relative binding affinity requires only six simulations, each of which takes 15 CPU h of computation on a single processor.