Studies of electrostatic energies in proteins

The importance of electrostatic effects as the primary correlation between structure and function of proteins as been long known. Electrostatic effects play a major role in various biological functions. However, obtaining quantitative correlation requires computational models that capture the microscopic nature of electrostatic effects in the very heterogeneous environments of macromolecules.; This dissertation examines electrostatic energies in proteins using different models, and considering different systems. Electrostatic energies are examined through calculations of pK_a's, solvation free energies and ionization states of key ionizable residues in different proteins. In addition the role of the protein electrostatic field in enzyme catalysis is examined by considering the relevant pK_a's shifts. The study of different system helps to establish a benchmark for electrostatic calculations and shade light on the requirements for proper validation of electrostatic models. It is demonstrated that the validation of electrostatic models is very problematic and can lead toward unjustified conclusions about the nature of electrostatic effects in proteins. Implicit models for evaluation of electrostatic energies in proteins include dielectric constants that represent effect of the protein environment. Unfortunately, the results obtained by such models are very sensitive to the value used for the dielectric constant. This work considers the meaning of the protein dielectric constants and the ways to determine their optimal values. Using our different models and a discriminative benchmark, we demonstrate that the protein dielectric constant, &egr;_p, is not a universal constant but simply a parameter that depends on the model used. It is also shown that &egr;_p represents the factors that are not considered explicitly. Furthermore, we demonstrate that the optimal dielectric constant for self-energies is not the optimal constant for charge-charge interactions. It found the PDLD/S-LRA model to be the optimal current model for pK _a's and solvation free energy calculations. This finding is further supported by using the PDLD/S-LRA model in estimating the electrostatic energies in the KscA ion channel as well as in studying the validity of the so called low barrier hydrogen bond (LBHB) hypothesis using the chymotrypsin from the serine protease family as the bench mark enzyme.