Computational and Theoretical Modeling of Two Dimensional Infrared Spectra of Peptides and Proteins

Abstract

Two-dimensional infrared (2D-IR) spectroscopy evolved out of the theoretical underpinnings of nonlinear methods to provide a means of investigating detailed molecular structure on ultrafast timescales. This opens up new possibilities for the study of protein folding and molecule-solvent interactions through greater spatial and temporal resolution. To study biomolecules, functional groups sensitive to the local environment known as infrared reporters are used to investigate activity at a particular site or sites of interest. Through these probes the analysis of dynamic species and site-specific structural information, previously inaccessible to direct observation, can elucidate key details of conformational changes that exert major influences on the activities of complex molecular systems.The broad objective of the research of the Tucker group is to obtain a description of the dynamic processes that lead to conformational changes at a chemical bond scale. A major component of 2D IR methods is the choice of vibrational probes used, which impacts the structural information provided about the larger surrounding environment. The type and placement of infrared reporter is highly system-specific, and developments within this area continue to open up new areas of inquiry for 2D IR experiments. My work has been towards providing an understanding of how these probes interact with their surroundings for the purpose of rational infrared probe design and insertion.The use of non-natural amino acid side chain probes has shown promise for use in tracking the dynamics of the side chain region of proteins. Studies performed in this work have demonstrated the ability of local amino acid modes to capture changes in local electric fields and the degree of hydration at distinct locations in proteins. The ring mode of tyrosine has particular utility as a naturally occurring probe that shows a high degree of sensitivity to its environment through solvent broadening, giving rise to applications in studies of folded and unfolded peptides/proteins. This is a promising step towards expanding the tools available to observe solvation and van der Waals forces during enzymatic and membrane-binding processes, amongst others.We have investigated the interaction between two potentially useful reporters for use in in nucleotides and small peptides: the cyano- and the azido- moieties. Theoretical models developed using this data demonstrate opportunities for monitoring structural changes within oligonucleotides and peptides. The relations between the intensity of the coupling of these reporters with spatial orientation and distance allows mapping of groups on the sub-nanometer scale with a sub-picosecond time frame, taking advantage of the powerful time-resolution of infrared methods.The advance of two-dimensional infrared spectroscopy depends upon the development of new techniques that take full advantage of new technology and theoretical methods. My work with the Tucker groups has been towards the application of computational work towards understanding the relationship between the behavior of the molecular groups of interest and the data collected from the infrared beam. This will hopefully continue to open up new and exciting possibilities for the further expansion of infrared techniques, which are speculated on in the final section. These findings represent a step forward in the development of 2D IR probe groups for the investigation of sub-picosecond processes in biomolecules.