Simulations of Phage T7 Capsid Expansion Reveal the Role of Molecular Sterics on Dynamics

Whitford, Paul C.; Jiang, Wen; Serwer, Philip

doi:10.3390/v12111273

Cited by 16 publications

(26 citation statements)

References 47 publications

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“…A complete description of this variant of the model is described in Ref. (40). The model is available for download at https://smog-server.org (SMOG2 force field repository name: SBM AA-amber-bonds).…”

Section: All-atom Structure-based Modelmentioning

confidence: 99%

Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion

Dodero-Rojas

Onuchic

Whitford

2021

eLife

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly contagious, and transmission involves a series of processes that may be targeted by vaccines and therapeutics. During transmission, host cell invasion is controlled by a large-scale (200–300 Å) conformational change of the Spike protein. This conformational rearrangement leads to membrane fusion, which creates transmembrane pores through which the viral genome is passed to the host. During Spike-protein-mediated fusion, the fusion peptides must be released from the core of the protein and associate with the host membrane. While infection relies on this transition between the prefusion and postfusion conformations, there has yet to be a biophysical characterization reported for this rearrangement. That is, structures are available for the endpoints, though the intermediate conformational processes have not been described. Interestingly, the Spike protein possesses many post-translational modifications, in the form of branched glycans that flank the surface of the assembly. With the current lack of data on the pre-to-post transition, the precise role of glycans during cell invasion has also remained unclear. To provide an initial mechanistic description of the pre-to-post rearrangement, an all-atom model with simplified energetics was used to perform thousands of simulations in which the protein transitions between the prefusion and postfusion conformations. These simulations indicate that the steric composition of the glycans can induce a pause during the Spike protein conformational change. We additionally show that this glycan-induced delay provides a critical opportunity for the fusion peptides to capture the host cell. In contrast, in the absence of glycans, the viral particle would likely fail to enter the host. This analysis reveals how the glycosylation state can regulate infectivity, while providing a much-needed structural framework for studying the dynamics of this pervasive pathogen.

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Section: All-atom Structure-based Modelmentioning

confidence: 99%

Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion

Dodero-Rojas

Onuchic

Whitford

2021

eLife

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“…In the current study, we developed a multi-basin structure-based model, where knowledge of the rotated and unrotated conformations (PDB: 3J77 and 3J78 [18]) were used to define the potential energy function. For this, we applied a SMOG-AMBER variant [29] of the SMOG class of structure-based models [28], where the potential energy is given by:…”

Section: Multi-basin Structure-based Modelmentioning

confidence: 99%

“…σ ij was set to 0.96 σ ij where σ ij is the interatomic distance between atoms that are in contact in the rotated (or unrotated) configuration. This scaling of contacts was introduced to avoid the artificial expansion of the ribosome that can arise from configurational entropy [29,32].…”

Section: Multi-basin Structure-based Modelmentioning

confidence: 99%

“…Simulations were performed using the GROMACS software package (v5.1.4) [33,34]. Force field files were generated using SMOG v2.3 [28] with the SBM_AA-amber-bonds force field templates [29], which are available through the smog-server.org force field repository. The contacts and dihedrals were then subsequently modified by custom scripts.…”

Section: Simulation Detailsmentioning

confidence: 99%

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The Dynamics of Subunit Rotation in a Eukaryotic Ribosome

et al. 2021

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Protein synthesis by the ribosome is coordinated by an intricate series of large-scale conformational rearrangements. Structural studies can provide information about long-lived states, however biological kinetics are controlled by the intervening free-energy barriers. While there has been progress describing the energy landscapes of bacterial ribosomes, very little is known about the energetics of large-scale rearrangements in eukaryotic systems. To address this topic, we constructed an all-atom model with simplified energetics and performed simulations of subunit rotation in the yeast ribosome. In these simulations, the small subunit (SSU; ∼1 MDa) undergoes spontaneous and reversible rotation events (∼8∘). By enabling the simulation of this rearrangement under equilibrium conditions, these calculations provide initial insights into the molecular factors that control dynamics in eukaryotic ribosomes. Through this, we are able to identify specific inter-subunit interactions that have a pronounced influence on the rate-limiting free-energy barrier. We also show that, as a result of changes in molecular flexibility, the thermodynamic balance between the rotated and unrotated states is temperature-dependent. This effect may be interpreted in terms of differential molecular flexibility within the rotated and unrotated states. Together, these calculations provide a foundation, upon which the field may begin to dissect the energetics of these complex molecular machines.

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“…In addition to these considerations, one may also wish to encode the bonded terms based on Amber 28 parameters, rather than those found in the structural model, as described recently for simulations of a viral capsid. 29 In terms of the user interface, all force field parameters are defined in the templates, while the glycan bonds are given through a PDB-file extension. Using the exact same files as input for SMOG 2, one can then generate the force field files for Gromacs (default behavior), or OpenMM (by issuing the flag).…”

Section: Applications Of Smog 2 and Opensmogmentioning

confidence: 99%

SMOG 2 and OpenSMOG: Extending the limits of structure-based models

Oliveira

Contessoto

Hassan

et al. 2021

Preprint

Self Cite

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Applying simulations with structure-based (Go-like) models has proven to be an effective strategy for investigating the factors that control biomolecular dynamics. The common element of these models is that some (or all) of the intra/inter-molecular interactions are explicitly defined to stabilize an experimentally-determined structure. To facilitate the development and application of this broad class of models, we previously released the SMOG 2 software package. This suite allows one to easily customize and distribute structure-based (i.e. SMOG) models for any type of polymer-ligand system. Since its original release, user feedback has driven the implementation of numerous enhancements. Here, we describe recent extensions to the software and demonstrate the capabilities of the most recent version, SMOG v2.4. Changes include new tools that aid user-defined customization of force fields, as well as an interface with the OpenMM simulation libraries (OpenSMOG v1.0). To illustrate the utility of these advances, we present several applications of SMOG2 and OpenSMOG, which include systems with millions of atoms, long polymers and explicit ions. We also highlight how one can incorporate non-structure-based (e.g. AMBER-based) energetics to define a hybrid class of models. The representative applications include large-scale rearrangements of the SARS-CoV-2 Spike protein, the HIV-1 capsid in the presence of explicit ions, and crystallographic lattices of ribosomes and proteins. In summary, SMOG 2 and OpenSMOG provide robust support for researchers who seek to apply structure-based models to large and/or intricate biomolecular systems.

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Simulations of Phage T7 Capsid Expansion Reveal the Role of Molecular Sterics on Dynamics

Cited by 16 publications

References 47 publications

Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion

Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion

The Dynamics of Subunit Rotation in a Eukaryotic Ribosome

SMOG 2 and OpenSMOG: Extending the limits of structure-based models

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