Protein Folding in Evolutionary Perspective

Shakhnovich, Eugene

Abstract

The overarching theme of the proposed research is to build a bridge between protein folding ? a molecular phenomenon ? and Biological phenotype in norm and in pathology. We will approach this important aim bottom up. First, we will achieve better understanding of universal principles and diversity of scenarios for folding of proteins of diverse structural classes. The way in which Biology communicates with proteins is through emergence and fixation of mutations. To this end the ultimate goal of this part of the research plan is to reach a clear understanding of how mutations at specific positions in protein sequences alter stability and folding dynamics. Armed with this new understanding of folding energetics and dynamics we venture into the study of the effect of perturbation of folding properties on function and pharmacodynamics of Interleukine 13 (IL-13) ? an important component of the immune system. Our focus here will be on computational selection of hydrocarbon staples in N-terminal -helix which will show most potency in antagonizing IL-13 (to minimize the IgE production in asthma pathology) and testing these computational predictions experimentally in vitro and in vivo. This will improve our understanding of how folding affects function ? in the context of functional protein-protein interactions of IL-13. The next stop in our journey will be to study association of proteins at concentration mimicking those in the cytoplasm. We will establish which mechanism(s) dominates formation of dimers and higher order structures (aggregation) and again our focus here will be on the impact of mutations on equilibrium and kinetic properties of fibril formation. Our next major step is the study of impact of selected mutations in cold-shock proteins on fitness of E.coli. Here we connect simulations, Bioinformatics and Systems Biology in the major quest to address one of the key Biological problems - how changes in protein folding thermodynamics and kinetics affect Niological phenotype.

Public Health Relevance

This theoretical and experimental study aims to discover how folding thermodynamics and kinetics of proteins affects Biological properties of cells which express them. It will help to identify alteration in proteins which cause diseases and find effective ways to design peptide based drugs to address pathologies.