Terascale ab initio molecular dynamics simulations of proton transfer and dissociation processes in chemical and biological systems

Ivaylo Nikolaev Ivanov, University of Pennsylvania


Calculation of pKas for acid/base reactions has been a long-standing goal of theoretical chemistry. Presented is a novel application of Car-Parrinello molecular dynamics to the problem of relative pKa determination. Our focus was on the second stage in the dissociation of histidine. Constrained dynamics has been used to calculate potentials of mean force (PMF) for the deprotonation reaction and to analyze the structural, electronic and dynamical transformations along the selected reaction coordinate. By integrating the PMF for the deprotonation of histidine and for a reference reaction—autodissociation of water—we obtain a value of 6.7, which is in excellent agreement with the experimental estimate of 6.1. In the second part of this dissertation, ab initio DFT methods were used to investigate the structural features of the binuclear enzyme arginase. Emphasis was placed on the crucial role of the second shell-ligand interactions. Orbitals involving the terminal Asp234 residue and the flexible μ-1,1-bridging Asp232 were found at high energies, suggesting weaker coordination. This is reflected in structural variability present in our models and is also consistent with recent experimental findings. Dynamical simulations demonstrate a labile coordination for these residues and carboxylate shifts for Asp234. Our results implicate Asp232 as a departing ligand in an observed proton transfer to Asp128. Direct AIMD simulation revealed low barrier proton transfer events from the bridging water molecule to the catalytically essential Asp128 residue. No proton transfer was observed in metal-depleted arginase. Constrained molecular dynamics has allowed comparison between the deprotonation free energy of the nucleophile for native and metal-depleted arginase. Finally, we investigated the mechanism for proton transfer of the OH− ion and found that it involved first solvation shell structural reorganization. This is in difference with the proposed mechanism for hydroxide mobility (N. Agmon), in which the rate limiting step is the breaking of a second-sphere H-bond in H7O4− to transiently form H 3O2−. Our results are in essential agreement with recent neutron diffraction experiments. The computed power and IR spectra are also in reasonable agreement with experimental data, despite the different microscopic structures observed, which may suggest a possible alternative interpretation of the experiments.

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Recommended Citation

Ivanov, Ivaylo Nikolaev, "Terascale ab initio molecular dynamics simulations of proton transfer and dissociation processes in chemical and biological systems" (2004). Dissertations available from ProQuest. AAI3152059.