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Computation of Entropy Contribution to Protein-Ligand Binding Free Energy

F. V. Grigoriev1*, S. V. Luschekina2, A. N. Romanov1, V. B. Sulimov1, and E. A. Nikitina3

1Research Computing Center of Lomonosov Moscow State University, 119992 Moscow, Russia; E-mail: fedor.grigoriev@gmail.com

2Orekhovich Institute of Biomedical Chemistry, ul. Pogodinskaya 10, 119121 Moscow, Russia; E-mail: sofia.luschekina@gmail.com

3Institute of Applied Mechanics, Russian Academy of Sciences, Leninsky pr. 32a, 119991 Moscow, Russia; E-mail: nikitina.ekaterina@gmail.com

* To whom correspondence should be addressed.

Received December 20, 2006; Revision received April 26, 2007
The entropy contribution DeltaS to protein-ligand binding free energy is studied for nine protein-lipid complexes. The entropy effect from the loss of the translational/rotational degrees of freedom (DeltaStr) is calculated using the ideal gas approach. The change in the vibrational entropy (DeltaSvib) is calculated using the effective quantum oscillator approach with frequencies derived from the coordinate covariance matrix, so the inharmonic effects are taken into account. The change in the entropy of solvation (DeltaSsolv) is considered using the binomial cell model (developed by the authors) for the hydrophobic effect. The entropy contribution from loss of conformations that are available for the free ligand (DeltaSconf) is also estimated. It is revealed that the negative in view of binding term DeltaStr is only partly compensated by increasing of DeltaSvib, so T(DeltaStr + DeltaSvib + DeltaSconf) < 0 for all complexes under investigation, but taking into account DeltaSsolv leads to significantly increased DeltaS. For all complexes except biotin-streptavidin, the results are found to be in reasonable agreement with experimental data.
KEY WORDS: protein-ligand complex, binding free energy, covariance matrix, vibration entropy

DOI: 10.1134/S0006297907070140