Protein-Ligand Interaction Energy-Based Entropy Calculations: Fundamental Challenges For Flexible Systems

Kohut, Gergely and Liwo, Adam and Bősze, Szilvia and Beke-Somfai, Tamás and Samsonov, Sergey A. (2018) Protein-Ligand Interaction Energy-Based Entropy Calculations: Fundamental Challenges For Flexible Systems. JOURNAL OF PHYSICAL CHEMISTRY B - CONDENSED MATTER MATERIALS SURFACES INTERFACES AND BIOPHYSICAL, 122 (32). pp. 7821-7827. ISSN 1520-6106

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Abstract

Entropy calculations represent one of the most challenging steps in obtaining the binding free energy in biomolecular systems. A novel computationally effective approach (IE) was recently proposed to calculate the entropy based on the computation of protein-ligand interaction energy directly from molecular dynamics (MD) simulations. We present a study focused on the application of this method to flexible molecular systems and compare its performance with well-established normal mode (NM) and quasiharmonic (QH) entropy calculation approaches. Our results raise substantial concerns on the general applicability of IE in terms of reproducibility, reasonable absolute values of the entropy and agreement with NM and QM approaches. IE shows significant variation in the computed entropy values depending on the MD frames chosen for calculations. These deviations render reproducibility of IE calculations to be far from sufficient. We conclude that IE is recommended to be used after substantial modifications with respect to its sampling methodology.

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