"Identifying Functionally Important Regions in Disease-Causing Disordered Proteins through Molecular Dynamics"
Department: Chemical Engineering Advisor: Jeetain Mittal
Despite the classic paradigm connecting protein function with well-defined structure, many naturally occurring functional proteins have recently been identified that lack a stable three-dimensional structure under physiological conditions. These proteins are commonly termed intrinsically disordered proteins (IDPs) or intrinsically unstructured proteins (IUPs). The aggregation propensity of several IDPs to form amyloid fibrils has been linked with various diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. It is very difficult to probe details of structural properties and early aggregation pathways of these proteins experimentally due to their heterogeneous ensemble and rapid aggregation in solution. Molecular simulations can provide fundamental insights into the properties of these systems at relevant length and time scales. We have used advanced replica exchange molecular dynamics (REMD) simulation to probe the structural characteristics of amylin, an IDP implicated in Type II Diabetes. This study of four closely related amino acid sequences of amylin has produced several notable outcomes. First, though these IDPs lack a stable tertiary structure, they do transiently sample structured states in solution. Furthermore, helical structure in one particular region, residues 7-16, may be partly responsible for differences in aggregation rates of these four amylin sequences. Structural differences in this region, which shares an identical amino acid sequence among the four polypeptides, indicate the significant unexpected influence of long-range contacts on the properties of IDPs. From our results, we can also conclude that MD simulation can be valuable in exploring molecular-level details of IDPs. These techniques hold significant promise in their utilization to determine structural characteristics which may be exploited in the development of effective small-molecule or peptide-based drugs for many diseases associated with amyloidosis of misfolded or disordered proteins.
About Cayla Miller:
Cayla is currently a junior at Lehigh University majoring in Chemical Engineering. Cayla presently continues her research under Dr. Jeetain Mittal, which focuses on study of intrinsically disordered proteins through molecular dynamics simulation. On campus, she is involved in the American Institute of Chemical Engineers, Tau Beta Pi, and the Society of Women Engineers, as well as heading Lehigh's needlecrafting club, Stitch. Upon graduation, Cayla plans to advance her studies in pursuit of a doctorate degree.