The empirical valence bond (EVB) methodology was developed by Warshel and collaborators [1,2], extending earlier ideas of Coulson and Danielsson [3].[1] A. Warshel and R. M. Weiss, J. Am. Chem. Soc. 102, 6218 (1980).

Proton transfer along 1D chains of water molecules inside carbon nanotubes is studied by simulations. Ab initio molecular dynamics and an empirical valence bond model yield similar structures and time scales. The proton mobility along 1D water chains exceeds that in bulk water by a factor of 40, but is reduced if orientational defects are present. Excess protons interact with hydrogen-bonding defects through long-range electrostatics, resulting in coupled motion of protons and defects.

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The structural determinants of the unusually low pK(a) values of Cys282 in human creatine kinase and Cys232 in alpha1-antitrypsin were studied computationally. We have demonstrated that hydrogen bonding to the cysteine residue is the prime determinant for both proteins. In the case of creatine kinase, the hydrogen bond donors are a serine side chain and an amide NH-group, while in alpha1-antitrypsin the donor is an amide NH. Each hydrogen bond lowers the pK(a) by between 0.8 and 1.5 pH units. The 1.1-unit lowering due to the Ser284-Cys282 hydrogen bond is in good agreement with the 1.2-unit difference between the Cys282 pK(a) value of wild-type and the S284A mutant of creatine kinase.

Computational modeling and its application in ligand screening and ligand receptor interaction studies play important roles in structure-based drug design. A series of sphingosine 1-phosphate (S1P) receptor ligands with varying potencies and receptor selectivities were docked into homology models of the S1P 1-5 receptors. These studies provided molecular insights into pharmacological trends both across the receptor family as well as at single receptors. This study identifies ligand recognition features that generalize across the S1P receptor family, features unique to the S1P 4 and S1P 5 receptors, and suggests significant structural differences of the S1P 2 receptor. Docking results reveal a previously unknown sulfur-aromatic interaction between the S1P 4 C5.44 sulfur atom and the phenyl ring of benzimidazole as well as π-π interaction between F3.33 of S1P 1,4,5 and aromatic ligands. The findings not only confirm the importance of a cation-π interaction between W4.64 and the ammonium of S1P at S1P 4 but also predict the same interaction at S1P 5 . S1P receptor models are validated for pharmacophore development including database mining and new ligand discovery and serve as tools for ligand optimization to improve potency and selectivity.