Research Project: Poli-Glutamin Dizilimlerinin HttNT-Sarmal Yapıları Aracılığıyla Kümelenmesi
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Contributors
Funders
ID
TB.00305
Authors
Sayar, Mehmet
Faculty Member
Publications
Assembly of huntingtin headpiece into α-helical bundles
(American Institute of Physics (AIP) Publishing, 2017) Özgür, Beytullah; Sayar, Mehmet; Department of Mechanical Engineering; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; Yes; College of Engineering; College of Sciences; GRADUATE SCHOOL OF SCIENCES AND ENGINEERING
Protein aggregation is a hallmark of neurodegenerative disorders. In this group of brain-related disorders, a disease-specific “host” protein or fragment misfolds and adopts a metastatic, aggregate-prone conformation. Often, this misfolded conformation is structurally and thermodynamically different from its native state. Intermolecular contacts, which arise in this non-native state, promote aggregation. In this regard, understanding the molecular principles and mechanisms that lead to the formation of such a non-native state and further promote the formation of the critical nucleus for fiber growth is essential. In this study, the authors analyze the aggregation propensity of Huntingtin headpiece (httNT), which is known to facilitate the polyQ aggregation, in relation to the helix mediated aggregation mechanism proposed by the Wetzel group. The authors demonstrate that even though httNT displays a degenerate conformational spectrum on its own, interfaces of macroscopic or molecular origin can promote the α-helix conformation, eliminating all other alternatives in the conformational phase space. Our findings indicate that httNT molecules do not have a strong orientational preference for parallel or antiparallel orientation of the helices within the aggregate. However, a parallel packed bundle of helices would support the idea of increased polyglutamine concentration, to pave the way for cross-β structures.
Representation of the conformational ensemble of peptides in coarse grained simulations
(AIP Publishing, 2020) Özgür, Beytullah; Sayar, Mehmet; N/A; Department of Mechanical Engineering; Graduate School of Sciences and Engineering; Yes; College of Engineering; GRADUATE SCHOOL OF SCIENCES AND ENGINEERING
In their native state, many proteins/peptides display an ensemble of conformations, rather than a unique tertiary structure. Novel experimental techniques have enabled a quantitative analysis of this structural heterogeneity. In molecular dynamics simulations, however, capturing this conformational ensemble quantitatively remains a major challenge even with all atom simulations. In coarse grained (CG) simulations, with fewer degrees of freedom, representation of the conformational ensemble becomes more problematic. Here, we revisit a CG model from our group, which was designed to address the conformational transferability problem by using the LKα14 peptide as a model system. The LKα14 peptide transitions from a random/unstructured state in dilute solution to a solely α-helical conformation upon aggregation as evidenced by circular dichroism. Here, we demonstrate that the structure/physics based approach, used in the original parameterization of our CG model, strongly depends on the reference system chosen and excluded volume interactions that are often considered to be of secondary importance. We first tune the excluded volume parameters by using both α-helix and β-sheet type structures as reference and then update the nonbonded interactions by using a goodness-of-fit metric for representation of the conformational ensemble of LKα14. We demonstrate that the updated model can recover the whole conformational ensemble quantitatively while maintaining the aggregation driven conformational transition. This balanced parametrization with regard to alternative secondary structures opens the door for the generalization of the CG model to other sequences, which we demonstrate on a β-sheet forming triblock peptide.
