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Topology, structures, and energy landscapes of human chromosomes.

ABSTRACT: Chromosome conformation capture experiments provide a rich set of data concerning the spatial organization of the genome. We use these data along with a maximum entropy approach to derive a least-biased effective energy landscape for the chromosome. Simulations of the ensemble of chromosome conformations based on the resulting information theoretic landscape not only accurately reproduce experimental contact probabilities, but also provide a picture of chromosome dynamics and topology. The topology of the simulated chromosomes is probed by computing the distribution of their knot invariants. The simulated chromosome structures are largely free of knots. Topologically associating domains are shown to be crucial for establishing these knotless structures. The simulated chromosome conformations exhibit a tendency to form fibril-like structures like those observed via light microscopy. The topologically associating domains of the interphase chromosome exhibit multistability with varying liquid crystalline ordering that may allow discrete unfolding events and the landscape is locally funneled toward "ideal" chromosome structures that represent hierarchical fibrils of fibrils.

SUBMITTER: Zhang B

PROVIDER: S-EPMC4434716 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Topology, structures, and energy landscapes of human chromosomes.

Zhang Bin B Wolynes Peter G PG

Proceedings of the National Academy of Sciences of the United States of America 20150427 19

Chromosome conformation capture experiments provide a rich set of data concerning the spatial organization of the genome. We use these data along with a maximum entropy approach to derive a least-biased effective energy landscape for the chromosome. Simulations of the ensemble of chromosome conformations based on the resulting information theoretic landscape not only accurately reproduce experimental contact probabilities, but also provide a picture of chromosome dynamics and topology. The topol ...[more]

PMID: 25918364

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Project description:The genetic missense A30P mutation of the wild-type ?-synuclein protein results in the replacement of the 30th amino acid residue from alanine (Ala) to proline (Pro) and was initially found in the members of a German family who developed Parkinson's disease. Even though the structures of these proteins have been measured before, detailed understanding about the structures and their relationships with free energy landscapes is lacking, which is of interest to provide insights into the pathogenic mechanism of Parkinson's disease. We report the secondary and tertiary structures and conformational free energy landscapes of the wild-type and A30P mutant-type ?-synuclein proteins in an aqueous solution environment via extensive parallel tempering molecular dynamics simulations along with thermodynamic calculations. In addition, we present the residual secondary structure component transition stabilities at the atomic level with dynamics in terms of free energy change calculations using a new strategy that we reported most recently. Our studies yield new interesting results; for instance, we find that the A30P mutation has local as well as long-range effects on the structural properties of the wild-type ?-synuclein protein. The helical content at Ala18-Gly31 is less prominent in comparison to the wild-type ?-synuclein protein. The ?-sheet structure abundance decreases in the N-terminal region upon A30P mutation of the wild-type ?-synuclein, whereas the NAC and C-terminal regions possess larger tendencies for ?-sheet structure formation. Long-range intramolecular protein interactions are less abundant upon A30P mutation, especially between the NAC and C-terminal regions, which is linked to the less compact and less stable structures of the A30P mutant-type rather than the wild-type ?-synuclein protein. Results including the usage of our new strategy for secondary structure transition stabilities show that the A30P mutant-type ?-synuclein tendency toward aggregation is higher than the wild-type ?-synuclein but we also find that the C-terminal and NAC regions of the A30P mutant-type ?-synuclein are reactive toward fibrillzation and aggregation based on atomic level studies with dynamics in an aqueous solution environment. Therefore, we propose that small molecules or drugs blocking the specific residues, which we report herein, located in the NAC- and C-terminal regions of the A30P mutant-type ?-synuclein protein might help to reduce the toxicity of the A30P mutant-type ?-synuclein protein.

Dataset Information

Topology, structures, and energy landscapes of human chromosomes.

Publications

Topology, structures, and energy landscapes of human chromosomes.

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