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Exploring the dynamics of four RNA-dependent RNA polymerases by a coarse-grained model.

ABSTRACT: In this article, we present a hybrid ENM/MARTINI coarse-grained model and examine the impact of reduced chemical detail on both static and dynamic properties by comparing against explicit atomistic simulations. This methodology complements the advanced molecular characterization and dynamics of proteins for medical and bioengineering applications by developing a fundamental understanding of how the motion and molecular characteristics of proteins, viruses, their precursors, and their interactions with the environment govern their behavior in different populations. As an example, we explore the dynamics of RNA-dependent RNA polymerases (RdRPs) from the following viruses: poliovirus, Coxsackie virus B3, human rhinovirus 16, and foot-and-mouth-disease virus. The hybrid coarse-grained model allows the microsecond time scales of interest for biological functions to be explored. Additionally, the ENM/MARTINI model captures the main features obtained from atomistic MD simulations for each of the RdRPs studied herein, including the higher flexibility of the pinky finger and thumb regions, as well as collective motions that might contribute significantly to the conformational transition between the open and closed states.

SUBMITTER: Shen H

PROVIDER: S-EPMC5718632 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Exploring the dynamics of four RNA-dependent RNA polymerases by a coarse-grained model.

Shen Hujun H Moustafa Ibrahim M IM Cameron Craig E CE Colina Coray M CM

The journal of physical chemistry. B 20121207 50

In this article, we present a hybrid ENM/MARTINI coarse-grained model and examine the impact of reduced chemical detail on both static and dynamic properties by comparing against explicit atomistic simulations. This methodology complements the advanced molecular characterization and dynamics of proteins for medical and bioengineering applications by developing a fundamental understanding of how the motion and molecular characteristics of proteins, viruses, their precursors, and their interaction ...[more]

PMID: 23157550

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Project description:Amyloid peptides are known to self-assemble into larger aggregates that are linked to the pathogenesis of many neurodegenerative disorders. In contrast to primary nucleation, recent experimental and theoretical studies have shown that many toxic oligomeric species are generated through secondary processes on a pre-existing fibrillar surface. Nucleation, for example, can also occur along the surface of a pre-existing fibril-secondary nucleation-as opposed to the primary one. However, explicit pathways are still not clear. In this study, we use molecular dynamics simulation to explore the free energy landscape of a free Abeta monomer binding to an existing fibrillar surface. We specifically look into several potential Abeta structural precursors that might precede some secondary events, including elongation and secondary nucleation. We find that the overall process of surface-dependent events can be described at least by the following three stages: 1. Free diffusion 2. Downhill guiding 3. Dock and lock. And we show that the outcome of adding a new monomer onto a pre-existing fibril is pathway-dependent, which leads to different secondary processes. To understand structural details, we have identified several monomeric amyloid precursors over the fibrillar surfaces and characterize their heterogeneity using a probability contact map analysis. Using the frustration analysis (a bioinformatics tool), we show that surface heterogeneity correlates with the energy frustration of specific local residues that form binding sites on the fibrillar structure. We further investigate the helical twisting of protofilaments of different sizes and observe a length dependence on the filament twisting. This work presents a comprehensive survey over the properties of fibril growth using a combination of several openMM-based platforms, including the GPU-enabled openAWSEM package for coarse-grained modeling, MDTraj for trajectory analysis, and pyEMMA for free energy calculation. This combined approach makes long-timescale simulation for aggregation systems as well as all-in-one analysis feasible. We show that this protocol allows us to explore fibril stability, surface binding affinity/heterogeneity, as well as fibrillar twisting. All these properties are important for understanding the molecular mechanism of surface-catalyzed secondary processes of fibril growth.

Dataset Information

Exploring the dynamics of four RNA-dependent RNA polymerases by a coarse-grained model.

Publications

Exploring the dynamics of four RNA-dependent RNA polymerases by a coarse-grained model.

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