A free energy calculation study of the effect of H→F substitution on binding affinity in ligand–antibody interactions
✍ Scribed by Minoru Saito; Isao Okazaki; Masayuki Oda; Ikuo Fujii
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- English
- Weight
- 281 KB
- Volume
- 26
- Category
- Article
- ISSN
- 0192-8651
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✦ Synopsis
Abstract
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