Intrinsically disordered proteins (IDPs) do not fold to a single three-dimensional structure under physiological conditions; however, still have biologically relevant functions in the cell. A significant fraction, more than 1/3rd, of eukaryotic proteins are fully or partially disordered. While IDPs in general perform critical functions in the cell, some of them are also closely related with serious human diseases, including Alzheimer’s, Parkinson’s, and type II diabetes. It is quite difficult to characterize the heterogeneous disordered ensemble of IDPs with available experimental techniques, and accurate all-atom simulations can be of significant help in interpreting and completing the experimental data. In this poster, I’ll highlight our ongoing research aimed at addressing following important questions related to the fundamental properties of disordered proteins:
i) How do protein sequence and temperature affect the properties of IDPs and unfolded proteins? To address this, we simulate five different protein sequences in aqueous solution for the systematic investigation of their characteristic polymer properties. We show that the sequence composition not only encodes properties at room temperature, but also determines their temperature-dependent characteristics.
ii) Where does the disease relevance of IDPs originate? To answer this question we simulate four different mutants of an IDP, Islet Amyloid Polypeptide (IAPP). While human IAPP forms amyloid aggregates in type II diabetes patients, other three mutants have different aggregation characteristics. We identify helix-promoting regions of aggregation prone IAPP monomers, which are potentially responsible for its amyloidogenic, i.e., disease related characteristics (1).
iii) How can we connect our simulations with the experiments? We parameterize a frequently used fluorophore pair of Forster resonance energy transfer (FRET) experiments, which is a useful experimental technique frequently used in IDP research. We have simulated several different unfolded proteins both in the absence and presence of the fluorophores. We find that the most structural properties of unfolded proteins remain unaffected in the presence of FRET chromophores. Our simulations also verify a commonly made critical assumption in FRET experiments, which is hard to justify otherwise (2).
1. Miller, Cayla, Gül H. Zerze, and Jeetain Mittal. "Molecular simulations indicate marked differences in the structure of amylin mutants, correlated with known aggregation propensity." J. Phys. Chem. B 117.50 (2013): 16066-16075.
2. Zerze, Gül H., Robert B. Best, and Jeetain Mittal. "Modest Influence of FRET Chromophores on the Properties of Unfolded Proteins." Biophys. J. 107.7 (2014): 1654-1660.
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