Mechanistic applications of volume profiles for chemical and biochemical processes

Pressure has a profound effect on both the speed and direction of chemical reactions; an effect which is inextricably linked to the change in volume of the system. Experimentally, this effect is described by the activation and reaction volumes, defined as the pressure derivatives of rate constants and equilibrium constants respectively. These quantities provide information about the relationships between the partial molar volumes of the reactant, product and transition state (TS). However, mechanistic interpretation of these volumes has posed a challenge due to the lack of an accurate computational technique for relating the geometrical structure of a reaction system to its volume. We have formulated a theoretical methodology that can be used to describe and predict the effects of pressure on reaction systems using the concept of a volume profile. These profiles, which detail how the partial molar volume of a system changes over the course of a reaction, can be calculated using the recently developed Archimedean displacement model of molecular volume. We explore two mechanistic applications of these profiles. The first is the calculation of Gibbs energy profiles at elevated pressures, allowing for the prediction of interesting and potentially useful chemical transformations that can occur with pressure. This technique was used to investigate high pressure structural transformations for a radical hydrogen transfer reaction, and also to examine the feasibility of pressure-driven molecular machines. The second application is the elucidation of TS structures from a comparison of the theoretical volume profile with the experimentally-determined activation volume. This technique is especially useful for systems with a high degree of conformational flexibility whose TSs are not readily identified using standard computational methods. We used this method to identify the TS ensemble for a flexible model chain, and for conformational changes in a cyclophane system. To apply this method to larger, more complex systems such as the unfolding of proteins, a reaction coordinate for the process is required. A proper definition for such a coordinate was investigated and some preliminary results are presented for biological systems