Molecular Computations for the Stabilization of Therapeutic Proteins

Abstract

Molecular computations based on quantum mechanics and statistical mechanics have been applied to the understanding and quantification of processes leading to the degradation of therapeutic proteins. In particular, we focus on oxidation and aggregation. Specifically, two reactions, hydrogen transfer of hydrogen peroxide to form water oxide and the oxidation of dimethyl sulfide (DMS) by hydrogen peroxide to form dimethyl sulfoxide, were studied as models of these processes in general. Reaction barriers of the hydrogen transfer of H₂O₂ are in average of 10 kcal/mol or higher than the oxidation of DMS. Therefore, a two step oxidation mechanism in which the transfer of hydrogen atom occurs first to form water oxide and the transfer of oxygen to substrate occurs as the second step, is unlikely to be correct. Our proposed oxidation mechanism does not suggest a pH dependence of oxidation rate within a moderate range around neutral pH (i.e. under conditions in which hydronium and hydroxide ions do not participate directly in the reaction), and it agrees with experimental observations over moderate pH values. In the field of aggregation, we have developed a relatively simple approach for computing the change in chemical potential of a protein upon addition of an excipient (cosolute) to the protein solution. We have also developed a general approach to the design of excipients to prevent aggregation and are currently testing it experimentally.