Dmitri Makarov of the University of Texas is funded by an award from the Theoretical and Computational Chemistry Program to study biological phenomena that involve the translocation of proteins through pores. Professor Makarov and his research group are developing computational tools and applying them to characterize the relationship between the structure of proteins and their resistance to co-translational unfolding. These computational studies complement recent single-molecule protein translocation experiments. An interdisciplinary workshop on single molecule dynamics that brings together theorists and experimentalists from a variety of disciplines is being planned.
Advances in molecular level understanding of the mechanisms of protein translocation may have a broad impact in terms of understanding the diseases that are related to defects in translocation machinery.
Proteins, the "workhorse" molecules that perform myriads of biological tasks in the living cell, are recycled or delivered to their targets through a process known as translocation. In the course of translocation, proteins must pass through narrow constrictions, which requires that they temporarily lose their shape and structure, i.e. unfold (Figure 1). This project has advanced computational algorithms and theories to model protein translocation and unfolding on a computer. A key challenge in modeling translocation is that the duration of this process is too long to be captured using brute-force computation. In reponse, the PI's group has developed a suite of computer algorithms that circumvent this difficulty by piecing together different stages of the process. Moreover, simple theories and formulas have been derived to estimate the timescales of this process without resorting to costly computation. The elusive, transient state where a protein is unfolded under physiological conditions has long escaped detailed characterization despite its crucial importantce in translocation and many other biological phenomena. This project, through extensive computer simulations performed at the Texas Advanced Computing Center and complemented by experimental studies by collaborators, has led to an accurate yet simple theoretical model for the structural and temporal properties of the unfolded state. Because the failure or disfunction of the cell translocation machinery is implicated in many diseases, such as Parkinson's and Huntington's diseases and Mohr-Tranebjaerg syndrome, the insights from this rsearch have important implications for healthcare. The computational algorithms developed in tis project are also applicable to a variety of problems in computational biophysics and materials science. This project involved joint, collaborative efforts with several experimental and computational groups across a broad range of disciplines, from comuptational mechanics and applied mathematics to biochemistry. As a result, graduate, undergraduate and high school students involved in this project have received truly interdisciplinary research experience, as well as an opportunity to communicate their research at national conferences.
