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Mesoscale All-Atom Influenza Virus Simulations Suggest New Substrate Binding Mechanism.

ABSTRACT: Influenza virus circulates in human, avian, and swine hosts, causing seasonal epidemic and occasional pandemic outbreaks. Influenza neuraminidase, a viral surface glycoprotein, has two sialic acid binding sites. The catalytic (primary) site, which also binds inhibitors such as oseltamivir carboxylate, is responsible for cleaving the sialic acid linkages that bind viral progeny to the host cell. In contrast, the functional annotation of the secondary site remains unclear. Here, we better characterize these two sites through the development of an all-atom, explicitly solvated, and experimentally based integrative model of the pandemic influenza A H1N1 2009 viral envelope, containing ?160 million atoms and spanning ?115 nm in diameter. Molecular dynamics simulations of this crowded subcellular environment, coupled with Markov state model theory, provide a novel framework for studying realistic molecular systems at the mesoscale and allow us to quantify the kinetics of the neuraminidase 150-loop transition between the open and closed states. An analysis of chloride ion occupancy along the neuraminidase surface implies a potential new role for the neuraminidase secondary site, wherein the terminal sialic acid residues of the linkages may bind before transfer to the primary site where enzymatic cleavage occurs. Altogether, our work breaks new ground for molecular simulation in terms of size, complexity, and methodological analyses of the components. It also provides fundamental insights into the understanding of substrate recognition processes for this vital influenza drug target, suggesting a new strategy for the development of anti-influenza therapeutics.

SUBMITTER: Durrant JD

PROVIDER: S-EPMC7048371 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Mesoscale All-Atom Influenza Virus Simulations Suggest New Substrate Binding Mechanism.

Durrant Jacob D JD Kochanek Sarah E SE Casalino Lorenzo L Ieong Pek U PU Dommer Abigail C AC Amaro Rommie E RE

ACS central science 20200219 2

Influenza virus circulates in human, avian, and swine hosts, causing seasonal epidemic and occasional pandemic outbreaks. Influenza neuraminidase, a viral surface glycoprotein, has two sialic acid binding sites. The catalytic (primary) site, which also binds inhibitors such as oseltamivir carboxylate, is responsible for cleaving the sialic acid linkages that bind viral progeny to the host cell. In contrast, the functional annotation of the secondary site remains unclear. Here, we better characte ...[more]

PMID: 32123736

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Project description:Focal adhesions are dynamic constructs at the leading edge of migrating cells, linking them to the extracellular matrix and enabling force sensing and transmission. The lifecycle of a focal adhesion is a highly coordinated process involving spatial and temporal variations of protein composition, interaction, and cellular tension. The assembly of focal adhesions requires the recruitment and activation of vinculin. Vinculin is present in the cytoplasm in an autoinhibited conformation in which its tail is held pincerlike by its head domains, further stabilized by two high-affinity head-tail interfaces. Vinculin has binding sites for talin and F-actin, but effective binding requires vinculin activation to release its head-tail associations. In migrating cells, it has been shown that the locations of vinculin activation coincide with areas of high cellular tension, and that the highest recorded tensions across vinculin are associated with adhesion assembly. Here, we use a structure-based model to investigate vinculin activation by talin modulated by tensile force generated by transient associations with F-actin. We show that vinculin activation may proceed from an intermediate state stabilized by partial talin-vinculin association. There is a low-force regime and a high-force regime where vinculin activation is dominated by two different pathways with distinct responses to force. Specifically, at zero or low forces, vinculin activation requires substantial destabilization of the main head-tail interface, which is rigid and undergoes very limited fluctuations, despite the other being relatively flexible. This pathway is not significantly affected by force; instead, higher forces favor an alternative pathway, which seeks to release the vinculin tail from its pincerlike head domains before destabilizing the head-tail interfaces. This pathway has a force-sensitive activation barrier and is significantly accelerated by force. Experimental data of vinculin during various stages of the focal adhesion lifecycle are consistent with the proposed force-regulated activation pathway.

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Mesoscale All-Atom Influenza Virus Simulations Suggest New Substrate Binding Mechanism.

Publications

Mesoscale All-Atom Influenza Virus Simulations Suggest New Substrate Binding Mechanism.

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