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A free energy calculation study of the effect of H→F substitution on binding affinity in ligand–antibody interactions
Author(s) -
Saito Minoru,
Okazaki Isao,
Oda Masayuki,
Fujii Ikuo
Publication year - 2005
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.20162
Subject(s) - chemistry , van der waals force , binding energy , ligand (biochemistry) , enthalpy , crystallography , solvation , interaction energy , gibbs free energy , stereochemistry , computational chemistry , solvent , molecule , thermodynamics , organic chemistry , receptor , biochemistry , physics , nuclear physics
Changes in binding affinity to catalytic antibody 6D9 of chloramphenicol phosphonate derivatives (CPDs) containing H or F were investigated by performing free energy calculations based on molecular dynamics simulations. We calculated the binding free energy, enthalpy, and entropy changes (ΔΔ G , ΔΔ H , and − T ΔΔ S ) attributable to H→F substitution by comparing results for CPDs containing a trifluoroacetylamino group (CPD‐F) or an acetylamino group (CPD‐H). The calculated ΔΔ G , ΔΔ H , and − T ΔΔ S values were −2.9, −6.3, and 3.5 kcal mol −1 and close to experimental values observed for a series of similar ligands, chloramphenicol phosphonates with F and H (−1.4, −3.5, and 2.1 kcal mol −1 ). Therefore, CPD‐F binds more strongly to 6D9 than does CPD‐H. To clarify the origin of the large difference in ΔΔ G , we apportioned the calculated values of ΔΔ G and Δ G for the associated and dissociated states into contributions from various atomic interactions. We found that the H→F substitution increased the binding affinity mainly by decreasing the hydration free energy and not by increasing favorable interactions with the antibody. The decreased hydration free energy of the ligand was mainly due to unfavorable coulombic interactions between the trifluoroacetylamino group and solvent waters, which increased the free energy of the dissociated state (by about 3.7 kcal mol −1 ). Also, the trifluoroacetylamino group slightly increased the free energy level of the associated state (about 0.8 kcal mol −1 ) because favorable van der Waals interactions compensated for unfavorable coulombic interactions with antibody atoms. In addition, the enthalpy and entropy changes, ΔΔ H and − T ΔΔ S (computationally −6.3 and 3.5 kcal mol −1 ), originated mainly from a decrease in hydration free energy in the dissociated state. The CPD‐F and CPD‐H ligands had substantially different structures in the dissociated and complexed states. © 2004 Wiley Periodicals, Inc. J Comput Chem 3: 272–282, 2005