Quantifying relative strengths of various components of noncovalent interactions is essential for understanding the process of molecular recognition and has practical application in structure-based drug design. We have analyzed structural and binding data associated with a large number of diverse protein-ligand complexes to derive quantitative estimates of relative strengths of common interaction types. Using regression analysis, we have quantified contributions to free energy of binding due to per unit contact surface area of lipophilic interactions, hydrogen bonds, salt-bridge, and other interactions involving π and amide systems. In agreement with several previous studies, non-specific lipophilic interactions contribute approximately 14 ± 1 cal mol-1 Å-2 to the free energy of binding. Strengths of specific polar interactions are highly context dependent, with buried interactions providing 3- to 5-fold greater contribution per unit surface area to the binding affinity than the corresponding solvent-exposed interactions. In the solvent inaccessible regions, the neutral-neutral and charge-neutral hydrogen bonds contribute 34 ± 7 and 54 ± 9 cal mol-1 Å-2, respectively, to the binding free energy, compared to 9 ± 6 (neutral-neutral) and 18 ± 9 (charge-neutral) cal mol-1 Å-2 in the solvent exposed region. We find that solvent inaccessible pi-stacking and XCH···π (X=N or O) interactions are remarkably strong and match those of buried charge-neutral hydrogen bonds, highlighting significance of these interactions in molecular recognition.

Quantifying key determinants of molecular recognition: Significance of pi interactions and charged hydrogen bonds in protein-ligand binding

249th National Meeting (2015)

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