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An electrostatic model based on charge density is proposed as a model for future force fields. The model is composed of a nucleus and a single Slater-type contracted Gaussian multipole charge density on each atom. The Gaussian multipoles are fit to the electrostatic potential calculated at the B3LYP/6-31G* and HF/aug-cc-pVTZ levels of theory and tested by comparing electrostatic dimer energies, intermolecular density overlap integrals, and permanent molecular multipole moments with their respective ab initio values. For the case of water, the atomic Gaussian multipole moments Qlmare shown to be a smooth function of internal geometry (bond length and angle), which can be approximated by a truncated linear Taylor series. In addition, results are given when the Gaussian multipole charge density is applied to a model for exchange−repulsion energy based on the intermolecular density overlap.

Abstract. Trocarin belongs to group D of prothrombin activators derived from snake venom of Tropidechis carinatus and is a rich non-hepatic source of Xa, the only known hepatic prothrombin activator. The structural and functional similarity with Xa makes trocarin an interesting target for exploring the structure-functional relationship with Xa. Herein we report a predicted complete three-dimensional all-atom structural model of trocarin equilibrated in explicit water using 4 ns of molecular dynamics simulation. The tertiary structure was modeled using the structure of human blood coagulation factor Xa. The conformational and structural features of trocarin are then compared with the X-ray crystal and solution simulation structures of human factor Xa. The modeled structure of trocarin has four individual domains (Gla, EGF1, EGF2 and SP) connected along the long axis with similar secondary structural elements to Xa. The simulations suggest that sodium ion binding in the serine protease domain is impaired in trocarin as compared to Xa. In contrast to Xa, for which the sodium ion forms an octahedral coordination network that brings two loop regions connecting four anti-parallel β-sheets together, we do not find a similar pattern of network in trocarin. We observe that the difference in the binding pattern of sodium ion leads to a ~2-Å "shrinkage" of the β2 strand (B2), in comparison to human Xa, as marked by a shorter distance between ¹⁸⁹Asp373 (S1-site residue) and ¹⁹⁵Ser379 (active-site residue) in the B2 strand. We propose that these differences may be linked to the experimentally observed lower amidolytic activity of trocarin as compared to Xa.

In this study we compare the binding energies of polycoordinated complexes of Zn2+within cavities composed of model “hard” (H2O, OH−) or “soft” (CH3SH, CH3S−) ligands. Ab initiosupermolecule computations are performed at the HF and MP2 levels using extended basis sets to determine the binding energies and their components as a function of: the number of ligands, ranging from three to six; the net charge of the cavity; and the “hard” versus “soft” character of the ligands. These ab initiocomputations are used to test the reliability of the SIBFA molecular mechanics procedure, originally formulated and calibrated on the basis of ab initiocomputations, for such charged systems. The SIBFA intermolecular interaction energies match the corresponding ab initiovalues using a coreless effective potential split‐valence basis set with a relative error of ≤3%. Extensions to binuclear Zn2+complexes, such as those that occur in the Zn‐binding sites of Gal4 and β‐lactamase proteins, are performed to test the applicability of the methodology for such systems. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 1011–1039, 2000

In this study we compare the binding energies of polycoordinated complexes of Zn²⁺ within cavities composed of model “hard” (H2O, OH⁻) or “soft” (CH3SH, CH3S⁻) ligands. Ab initio supermolecule computations are performed at the HF and MP2 levels using extended basis sets to determine the binding energies and their components as a function of: the number of ligands, ranging from three to six; the net charge of the cavity; and the “hard” versus “soft” character of the ligands. These ab initio computations are used to test the reliability of the SIBFA molecular mechanics procedure, originally formulated and calibrated on the basis of ab initio computations, for such charged systems. The SIBFA intermolecular interaction energies match the corresponding ab initio values using a coreless effective potential split-valence basis set with a relative error of ≤3%. Extensions to binuclear Zn²⁺ complexes, such as those that occur in the Zn-binding sites of Gal4 and β-lactamase proteins, are performed to test the applicability of the methodology for such systems. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 1011–1039, 2000

An active sulfotransferase (ST, residues 558–882) domain of the human heparan sulfate N‐deacetylase/N‐sulfotransferase (hHSNST) has been identified by aligning the amino acid sequence of hHSNST to that of mouse estrogen sulfotransferase (EST). The bacterially expressed ST domain transfers the 5′‐sulfuryl group of 3′‐phosphoadenosine‐5′‐phosphosulfate (PAPS) to only deacetylated heparin with an efficiency similar to that previously reported for the purified rat HSNST. Moreover, the KmPAPS(2.1 μM) of the ST domain is also similar to that of the rat enzyme. Lys48is a key residue in mEST catalysis. The residue corresponding to Lys48is conserved in all known heparan sulfate sulfotransferases (Lys614in the ST domain of hHSNST). Mutation of Lys614to Ala abolishes N‐sulfotransferase activity, indicating an important catalytic role of Lys614in the ST domain. Crystals of the ST domain have been grown (orthorhombic space group P21212) with diffraction to 2.5 A resolution.