The objective of this project is to establish a QM/MM methodology for the prediction and interpretation of protein pKa's that have unusual values and/or are difficult to model with current methodologies. The methodology will be applied to three proteins (turkey ovomucoid third domain, ubiquitin, and xylanase) for which detailed experimental studies of the factors that influence pKa's have been performed. A three-layered computational (QM/MM/LPBE) methodology for protein pKa prediction will be developed. The ionizable residue and its immediate environment will be treated by ab initio electronic structure (QM) methods (including energy minimization and harmonic vibrational analysis). The rest of the protein will be treated with a polarizable, multipole-based electrostatic model (MM) derived specifically for each protein by separate ab initio calculations. The bulk solvent will be treated by a very accurate solution of the linearized Poisson-Boltzmann equation (LPBE). The combined use of this new method with current methods will contribute significantly to the experimental design of proteins with greater stability or new functions.
This research is at the intersection of molecular physics, quantum chemistry, and structural biology, and will therefore offer important cross-disciplinary training to the postdoctoral associate, graduate student, and undergraduate students involved. Their training is further enhanced by tight collaboration with experimental research groups. The resulting scientists will be well versed in both the mathematical foundations and practical aspects of quantum chemistry (including algorithm development and parallelization) and macromolecular modeling within the context of an interdisciplinary research environment. Furthermore, all algorithmic developments will be implemented in the quantum chemistry program GAMESS, which is distributed free of charge to the scientific community. This work is funded jointly by the Theoretical and Computational Chemistry Program in the Chemistry Division and the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences.
