Mor M. Naor

Car-Parrinello molecular dynamics simulation of the calcium ion in liquid water

Structural and dynamical properties of the Ca 2þ ion in liquid water were studied using Car–Parrinello molecular dynamics. We found that the coordination number of the calcium ion fluctuates between 7 and 8. During a 14-ps simulation, water molecule exchange between the first solvation shell and the bulk was observed. 2003 Elsevier Science B.V. All rights reserved.

Determinants of cysteine pKa values in creatine kinase and α1‐antitrypsin

The structural determinants of the unusually low pKa values of Cys282 in human creatine kinase and Cys232 in α1‐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 α1‐antitrypsin the donor is an amide NH. Each hydrogen bond lowers the pKa 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 pKa value of wild‐type and the S284A mutant of creatine kinase. Proteins 2004.

Molecular Recognition in the Sphingosine 1-Phosphate Receptor Family

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 pi-pi interaction between F3.33 of S1P(1,4,5) and aromatic ligands. The findings not only confirm the importance of a cation-pi 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.

Dipole moment of water molecules in narrow pores

We use ab initio molecular dynamics simulation to calculate the dipole moment of water molecules in one-dimensional hydrogen bonded chains in narrow pores. The electronic charges are partitioned among the water molecules using maximally localized Wannier functions. For water molecules confined t o the interior of a carbon nanotube we find an average dipole moment of about 2.7 D, almost 10 % lower than the dipole moment of water molecules in the liquid phase calculated with the same method. The value of the water dipole moment in hydrogen bonded chains determines the effective interaction of excess protons and hydrogen bonding defects in the water chain. Using the dipole moment from our simulations we obtain an effective charge of 0.4e and -0.4e for the D-defect and the L-defect, respectively, and an effective charge of 0.6e for an excess proton in the chain.