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J Am Chem Soc. 2016 May 4;138(17):5722-8. doi: 10.1021/jacs.6b02682. Epub 2016 Apr 20.

Interaction Entropy: A New Paradigm for Highly Efficient and Reliable Computation of Protein-Ligand Binding Free Energy.

Duan L1,2, Liu X1, Zhang JZ1,3,4,5.

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Department of Physics, College of Chemistry and Molecular Engineering, East China Normal University , Shanghai 200062, China.
School of Physics and Electronics, Shandong Normal University , Jinan 250014, China.
NYU-ECNU Center for Computational Chemistry at NYU Shanghai , Shanghai 200062, China.
Department of Chemistry, New York University , New York, New York 10003, United States.
Collaborative Innovation Center of Extreme Optics, Shanxi University , Taiyuan, Shanxi 030006, PRC.


Efficient and reliable calculation of protein-ligand binding free energy is a grand challenge in computational biology and is of critical importance in drug design and many other molecular recognition problems. The main challenge lies in the calculation of entropic contribution to protein-ligand binding or interaction systems. In this report, we present a new interaction entropy method which is theoretically rigorous, computationally efficient, and numerically reliable for calculating entropic contribution to free energy in protein-ligand binding and other interaction processes. Drastically different from the widely employed but extremely expensive normal mode method for calculating entropy change in protein-ligand binding, the new method calculates the entropic component (interaction entropy or -TΔS) of the binding free energy directly from molecular dynamics simulation without any extra computational cost. Extensive study of over a dozen randomly selected protein-ligand binding systems demonstrated that this interaction entropy method is both computationally efficient and numerically reliable and is vastly superior to the standard normal mode approach. This interaction entropy paradigm introduces a novel and intuitive conceptual understanding of the entropic effect in protein-ligand binding and other general interaction systems as well as a practical method for highly efficient calculation of this effect.

[Indexed for MEDLINE]

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