Huntington’s disease is a member of a group of neurodegenerative diseases called polyglutamine diseases, which are characterized by mutations that cause elongated polyglutamine repeats in proteins. Mutated proteins misfold and aggregate into amyloid-like fibrils in the neuron. Experimental techniques are used to analyze the structure of polyglutamine systems, but these methods lack the sensitivity to reveal the behavior of individual peptides on the atomic scale. For this reason, computer simulations are used to fully characterize the structure, dynamics, and energetics of these systems. In the field, short polyglutamine peptides, Q&lt;30, are commonly used as models for study due to their simple sequence and the fact that they form fibrils similar to longer polypeptides. In previous research, we successfully used metadynamics MD simulations to identify low energy structures for the peptide D2Q10K2. Stable β-hairpin, PPII-rich, and collapsed random coil structures populate this peptide’s conformational free energy landscape. The process by which D2Q10K2 polypeptides dimerization, and subsequently polymerize, into aggregates is unknown. Elucidating this process will shed light on the aggregation scheme of polyglutamine peptides and will also aid in the study of other amyloidoses. In this work, we sought to investigate the free energy and conformation of D2Q10K2 dimerization, designing simulations based on what we know about the monomeric structure of these peptides. Utilizing adaptive biasing force and umbrella sampling MD simulations, we calculated the potential of mean force (PMF) of dimerization for various conformations of monomer. β-hairpin structures have been proposed in multiple studies as the nucleating unit for fibril formation. We will use these simulations to test this hypothesis; results from these simulations will be presented.

Evaluating free energies of dimerization of short polyglutamine peptides with molecular dynamics simulations

251st National Meeting (2016)

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