Molecular mechanics force-field development for amino acid zwitterions.

Understanding the conformational flexibility of amino acid zwitterions (ZWs) and their associated conformational energies is crucial for predicting their interactions in biological systems. Gas-phase ab initio calculations of ZWs are intractable. Molecular mechanics (MM), on the other hand, is able to handle large systems but lacks the necessary force field parameters to model ZWs. To develop force field parameters that are able to correctly model ZW geometries and energetics we used a novel combinatorial approach: amino acid ZWs were broken down structurally into key functional components, which were parameterized separately. Møller-Plesset second-order perturbation calculations on small carboxylates, on the glycine cation, and on novel hydrogen bonded systems, coupled with available experimental data, were used to generate MM3(2000) ZW parameters (Allinger N. L.; Yuh, Y. H.; Lii, J.-H. J Am Chem Soc 1989, 111, 8551). The MM3 results from this combinatorial approach gave geometries that are in good agreement with neutron diffraction experiments, plus their frequencies and energies appear to be reasonably modeled. Current limitations and future development of MM force fields are discussed briefly.

Solvent interactions determine carbohydrate conformation.

The relationship between the three-dimensional structures of oligosaccharides and polysaccharides and their biological properties has been the focus of many recent studies. The overall conformation of an oligosaccharide depends primarily on the orientation of the torsion angles (phi, psi, and omega) between glycosyl residues. Numerous experimental studies have shown that in glucopyranosides the omega-torsion angle (O(6)-C(6)-C(5)-O(5)) displays a preference for gauche orientations, in disagreement with predictions based on gas-phase quantum mechanics calculations. In contrast, the omega-angle in galactopyranosides displays a high proportion of the anti-orientation. For oligosaccharides containing glycosidic linkages at the 6-position (1-->6 linked), variations in rotamer population have a direct effect on the oligosaccharides' structure and function, and yet the physical origin of these conformational preferences remains unclear. Although it is generally recognized that the gauche effect in carbohydrates is a solvent-dependent phenomenon, the mechanism through which solvent induces the gauche preference is not understood. In the present work, quantum mechanics and solvated molecular dynamics calculations were performed on two representative carbohydrates, methyl alpha-D-glucopyranoside and methyl alpha-D-galactopyranoside. We show that correct reproduction of the experimental rotamer distributions about the omega-angles is obtained only after explicit water is included in the molecular dynamics simulations. The primary role of the water appears to be to disrupt the hydrogen bonding within the carbohydrate, thereby allowing the rotamer populations to be determined by internal electronic and steric repulsions between the oxygen atoms. The results reported here provide a quantitative explanation of the conformational behavior of (1-->6)-linked carbohydrates.

Quantum mechanical study of the nonbonded forces in water-methanol complexes.

The water-methanol dimer can adopt two possible configurations (WdM or MdW) depending on whether the water or the methanol acts as the hydrogen bond donor. The relative stability between the two configurations is less than 1 kcal/mol, and as a result, this dimer has been a challenging system to investigate using either theoretical or experimental techniques. In this paper, we present a systematic study of the dependence of the geometries, interaction energies, and harmonic frequencies on basis sets and treatment of electron correlation for the two configurations. At the highest theory level, MP2/aug-cc-pVQZ//MP2/aug-cc-pVTZ, interaction energies of -5.72 and -4.95 kcal/mol were determined for the WdM and MdW configurations, respectively, after correcting for basis set superposition error using the Boys-Bernardi counterpoise scheme. Extrapolating to the complete basis set limit resulted in interaction energies of -5.87 for WdM and -5.16 kcal/mol for MdW. The energy difference between the two configurations is larger than the majority of previously reported values, confirming that the WdM complex is preferred, in agreement with experimental observations. The effects that electron correlation have on the geometry were investigated by performing optimization at the MP2(full), MP4, and CCSD levels of theory. The approach trajectories for the formation of each dimer configuration are presented and the importance of these trajectories in the development of parameters for use in classical force fields is discussed.

Density functional and Ab initio studies on N-acetylduocarmycin SA: insight into its DNA interaction properties.

Density functional (DF) and Møller-Plesset second order perturbation (MP2) calculations were carried out on N-acetylduocarmycin SA (N-Ac-DSA), an analogue of a series of potent antitumor antibiotics that include the duocarmycins. These computational methods were used to investigate the degree of ground state destabilization of duocarmycins that would result upon binding to DNA. Ground state destabilization has been proposed as the origin of the ligand's enhanced rate of alkylation by more than a millionfold. The conformations of the 'Unbound' and 'DNA-Bound' N-Ac-DSA were generated using available geometric data for duocarmycin SA. Specifically, the dihedral angles chi1/chi2 were locked at 6.9 degrees/4.5 degrees for the Unbound and 22.0 degrees/11.0 degrees for the Bound form. The structures were optimized using DF theory, with subsequent MP2 calculations to improve the electronic energies. All of the calculations were performed on the unprotonated (1) as well as the C6-carbonyl protonated form (2). The results showed that the ground state destabilization energies of the Unbound and Bound forms, for the unprotonated and protonated series, were fairly small (< 0.8 kcal/mol). Similarly, the difference in the electronic nature of the Unbound and Bound forms, as indicated by changes in bond lengths and charge density, were also small. In summary, it appears that twisting of two key torsional angles, the concomitant ground state destabilization, and C6-carbonyl protonation may not fully account for the significant rate increase of adenine-N3 alkylation upon binding to DNA.