Research

Dynamin Membrane Fission

Dynamin is able to cause lipid vessicle membrane fission by undergoing a large conformational change when it hydrolyses GTP. Membrane remodeling, protein-protein interactions, and chemical reactions all work together to create an oligomeric coat of dynamin proteins around the vesicle that ultimately disrupts the lipid membrane to the point that the vesicle is released. Much experimental work has been done to understand this process, but there is no clear consensus on what the ultimate mechanism is for dynamin induced membrane scission. Molecular dynamics approaches have been used to understand the conformational changes in the protein resulting from the formation of protein dimers or tetramers; however, these approaches are not able to take into account the large-scale conformational changes in the protein resulting from enzymatic hydrolysis of GTP. Additionally, they do not include interactions with the lipid membrane. To determine the mechanism of membrane fission, a multiscale approach is needed that can systematically incorporate all of the sub-processes that occur at very different length-scales and still maintain the underlying physics and chemistry.

Alpha synuclein aggregation

Mutations in the neuronal protein α-synuclein lead to misfolded structures that are associated with the development of Parkinson’s disease. These misfolded structures, which occur in both the membrane and in solution, can cause the formation of protein aggregates that result in neurodegenerative toxicity. Although it is known that the toxicity of the protein is due to a specific sequence of amino acid residues, the molecular process leading to the formation of these protein aggregates is not fully known. Molecular dynamics (MD) simulations of α-synuclein provide a powerful tool to understand both the structure and oligomerization of the proteins at a molecular level; however, the formation of protein aggregates involves system sizes and timescales beyond the scope of standard MD methods. Instead, a multiscale approach is needed that uses low resolution, coarse-grained MD simulations of the full oligomerization process to guide smaller all-atom MD simulations. These studies can be combined with enhanced sampling techniques to understand the thermodynamics of oligomer formation in a multiscale way that is physically, chemically, and biologically relevant.

Huntingtin Protein Fibrilization

Huntington’s disease is a devastating neurological disorder that currently has limited therapeutic options. The disease results from a CAG mutation in the exon-1 region of the huntingtin (Htt) gene that causes an elongation of the polyglutamine (polyQ) tract in the N-terminal domain of the Htt protein. Diagnosis of the disease is done by determining the length of the polyQ tract. The non-pathogenic, wild type protein (wtHtt) has a polyQ length of 22 or fewer residues. The pathogenic threshold polyQ length for the disease is ~36 glutamine (Q) residues, with symptoms being inversely dependent on Q-length and usually manifesting in middle age. Although the diagnosis is clear, the cause of the disease is not known. The strong dependence of Q-length to the disease suggests that it must play some role in disease activity, but so far there is no clear consensus. Coarse-grained models can be used to study how monomers form both fibrils and other aggregates, which can then be used to run CG-guided all-atom simulations that will elucidate the molecular interactions that lead to fibrilization.