• Protein Aggregation Diseases. The aggregation of peptides or proteins into amyloid fibril morphologies is associated with over 20 human diseases, including Alzheimer’s, Parkinson’s, and Type II Diabetes diseases. Notwithstanding that the proteins that comprise the disease-related aggregates are dissimilar with respect to amino acid sequence, the aggregates themselves take on surprisingly consistent morphologies that are rich in β-strands orthogonal to the fibril axis, which organize further into intermolecular β-sheets that can extend to microns in length. Although early attention focused on toxicity of the amyloid fibrils as the primary cause of disease, there is strong evidence accumulating that oligomers formed during early aggregation events are actually the major cytotoxic species. This shift underscores our approach to develop an understanding of the early aggregation process that ultimately leads to the amyloid fibril assemblies both in vitro and in vivo and how oligomers vs. mature fibrils interact with cell membranes with varying concentrations of cholesterol, lipids, and surface sugar chemistry.

• Protein Folding Mechanisms and Relation to Function. In protein folding, the self-assembly mechanism of individual proteins is intimately tied to their function; for example it may be the key for rationalizing the underlying sequence-dependence of what defines aggregation disease proteins indicted in Alzheimer’s and Parkinson’s disease. The primary hypothesis of our recent work, and the focus of proposed work, is that the structural signatures of the denatured state ensemble (DSE) which show native contacts that are delocalized across the protein fold upon mutation should correlate with slower aggregation rates. A corollary of this work is that early intermediates in folding that are structurally delocalized would slow aggregation further.

• Multi-Protein Complexes. Signaling cascades are activated and regulated by spatially localized multi-protein complexes.  It is becoming increasingly clear that the role of any specific adaptor, binding, catalytic or signaling protein is only meaningful depending on its context: what are the co-constituents of the protein complex with which it associates, what is the temporal order in which the spatially organized multi-protein complex is formed, and how are these effected by the surrounding environmental conditions? This complexity cannot often be easily dissected using experimental biochemical techniques. We are developing a multiscale models of molecular electrostatics and coarse-grained stochastic dynamics approaches, in order to provide insight and experimental guidance in regards to structure, formation and function of multi-protein complexes.



• Protein Fold and Structure Prediction. A protein’s structural fold is highly correlated with, and informative about, it’s functional role in the cell. The prediction of a protein’s self-assembly process into this functional state is known as the protein folding problem. The protein folding problem in its most pragmatic guise is to predict the full three-dimensional structure of the protein molecule given a protein-solvent free energy surface and amino acid sequence as input. The “rugged landscape” topography of this surface defines the underlying difficulty in that the native structure minimum, usually the global minimum, must be discriminated from other minima whose number rises exponentially with the number of amino acids in the sequence. The development of first principle energy landscape approaches provides an important alternative to methods that rely on known protein folds for predicting new protein structures.







• Hydration Forces and Dynamics and Protein Function. The observation that water dynamics near protein surfaces shows non-exponential thermal relaxation processes has led to active exploration in two intimately related areas: whether protein-water systems bear sufficient analogy and therefore are informative about the nature of glass formers, and what are the biological implications if such a relationship existed between the two systems. It would seem that water on this planet has played a highly influential, but still largely hidden, role of exerting evolutionary pressure to adapt amino acid sequences (and therefore protein folds) to exploit its many anomalies for enhanced biological function- a possibility that merits further and deeper investigation.



See Research Areas for more in-depth descriptions of the research areas.