Prefusion spike protein conformational changes are slower in SARS-CoV-2 than in SARS-CoV-1

Kumar, Vivek Govind; Ogden, Dylan S.; Isu, Ugochi; Polasa, Adithya; Losey, James; Moradi, Mahmoud

doi:10.1016/j.jbc.2022.101814

Cited by 20 publications

(27 citation statements)

References 91 publications

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“…139, 140 Another insightful atomistic simulation study of the kinetics of conformational changes in the SARS-CoV-2 and CoV-1 S proteins showed that a salt bridge R319-D745 between the RBD of the active up protomer and the S2 region in the CoV-2 S protein contributes to the relative stability of the active spike state and the differential dynamic behavior between SARS CoV-2 and SARS CoV-1 spike trimers. 141…”

Section: Resultsmentioning

confidence: 99%

Hierarchical Computational Modeling and Dynamic Network Analysis of Allosteric Regulation in the SARS-CoV-2 Spike Omicron Trimer Structures: Omicron Mutations Cooperate to Allosterically Control Balance of Protein Stability and Conformational Adaptability

Verkhivker

Agajanian

Kassab

et al. 2022

Preprint

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Structural and computational studies of the Omicron spike protein in various functional states and complexes provided important insights into molecular mechanisms underlying binding, high transmissibility, and escaping immune defense. However, the regulatory roles and functional coordination of the Omicron mutations are poorly understood and often ignored in the proposed mechanisms. In this work, we explored the hypothesis that the SARS-CoV-2 spike protein can function as a robust allosterically regulated machinery in which Omicron mutational sites are dynamically coupled and form a central engine of the allosteric network that regulates the balance between conformational plasticity, protein stability, and functional adaptability. In this study, we employed coarse-grained dynamics simulations of multiple full-length SARS-CoV-2 spike Omicron trimers structures in the closed and open states with the local energetic frustration analysis and collective dynamics mapping to understand the determinants and key hotspots driving the balance of protein stability and conformational adaptability. We have found that the Omicron mutational sites at the inter-protomer regions form regulatory clusters that control functional transitions between the closed and open states. Through perturbation-based modeling of allosteric interaction networks and diffusion analysis of communications in the closed and open spike states, we quantify the allosterically regulated activation mechanism and uncover specific regulatory roles of the Omicron mutations. The network modeling demonstrated that Omicron mutations form the inter-protomer electrostatic bridges that connect local stable communities and function as allosteric switches of signal transmission. The results of this study are consistent with the experiments, revealing distinct and yet complementary role of the Omicron mutational sites as a network of hotspots that enable allosteric modulation of structural stability and conformational changes which are central for spike activation and virus transmissibility.

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Section: Resultsmentioning

confidence: 99%

Hierarchical Computational Modeling and Dynamic Network Analysis of Allosteric Regulation in the SARS-CoV-2 Spike Omicron Trimer Structures: Omicron Mutations Cooperate to Allosterically Control Balance of Protein Stability and Conformational Adaptability

Verkhivker

Agajanian

Kassab

et al. 2022

Preprint

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“…The combination of equilibrium and non-equilibrium MD simulations has proven effective for investigating biological challenges. 12,56–64 In this work, the YidC independent insertion mechanism was studied using non-equilibrium targeted MD (TMD) as implemented within the colvars module of NAMD. 65 TMD simulation was performed on the final conformation of the pose 1 system obtained from the 550 ns equilibrium trajectory in order to transfer the Pf3 peptide to the periplasmic side of the membrane, as seen in pose 2.…”

Section: Methodsmentioning

confidence: 99%

An Investigation of the YidC-Mediated Membrane Insertion of Pf3 Coat Protein Using Molecular Dynamics Simulations

Polasa

Hettige

Immadisetty

et al. 2022

Preprint

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YidC is a membrane protein that facilitates the insertion of newly synthesized proteins into lipid membranes. Through YidC, proteins are inserted into the lipid bilayer via the SecYEG-dependent complex. Additionally, YidC functions as a chaperone in protein folding processes. Several studies have provided evidence of its independent insertion mechanism. However, the mechanistic details of the YidC independent protein insertion mechanism remain elusive at the molecular level. This study elucidates the insertion mechanism of YidC at an atomic level through a combination of equilibrium and non-equilibrium molecular dynamics (MD) simulations. Different docking models of YidC-Pf3 in the lipid bilayer were built in this study to better understand the insertion mechanism. To conduct a complete investigation of the conformational difference between the two docking models developed, we used classical molecular dynamics simulations supplemented with a non-equilibrium technique. Our findings indicate that the YidC transmembrane (TM) groove is essential for this high-affinity interaction and that the hydrophilic nature of the YidC groove plays an important role in protein transport across the cytoplasmic membrane bilayer to the periplasmic side. At different stages of the insertion process, conformational changes in YidC’s TM domain and membrane core have a mechanistic effect on the Pf3 coat. Furthermore, during the insertion phase, the hydration and dehydration of the YidC’s hydrophilic groove are critical. These demonstrate that Pf3 interactions with the membrane and YidC vary in different conformational states during the insertion process. Finally, this extensive study directly confirms that YidC functions as an independent insertase.

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“…In the NPT ensemble at 310 K, 1 µ s of equilibrium MD simulations were performed under periodic boundary conditions for each system. In the simulations, a Langevin integrator with a damping coefficient of γ =0.5 ps − 1 and 1 atm pressure was maintained using the Nose-Hoover Langevin piston method 56,57 18,58–67 .…”

Section: Methodsmentioning

confidence: 99%

“…The preliminary simulations were run on TACC Stampede supercomputer. Subsequently, the production run for each model was increased to 400 ns with a timestep of 2.5 fs on Anton2 58 . Every 240 picoseconds, conformations were gathered on Anton2.…”

Section: Methodsmentioning

confidence: 99%

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Deciphering the Inter-domain Decoupling in the Gram-negative Bacterial Membrane Insertase

Polasa

Moradi

2022

Preprint

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YidC is a protein found in membranes that plays an important role in the process of inserting newly generated proteins into lipid membranes. The SecYEG-dependent complex is responsible for inserting proteins into the lipid bilayer, and this process is facilitated by YidC. In addition, YidC acts as a chaperone during the folding processes of proteins. Multiple investigations have conclusively shown that the gram-positive bacterium YidC has SecY-independent insertion mechanisms. Through the use of microsecond level all-atom molecular dynamics simulations, we have carried out the first in-depth investigation of the YidC protein originating from gram-negative bacteria. This research sheds light on the significance of several structural areas related to YidC at an atomic level by utilizing equilibrium molecular dynamics (MD) simulations. In this research, multiple models of YidC inside the lipid bilayer were constructed in order to achieve a deeper understanding of the critical role of the C2 loop and the extra periplasmic domain present in gram-negative YidC. According to the results of our research, the C2 loop is responsible for the overall stabilization of the protein, most notably in the transmembrane region, and it also has an allosteric influence on the periplasmic domain. We have found critical interactions that contribute to the stability of the protein as well as its functional aspect. Finally, our study provides a hypothetical SecY-independent insertion mechanism for gram-negative bacterial YidC.

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Prefusion spike protein conformational changes are slower in SARS-CoV-2 than in SARS-CoV-1

Cited by 20 publications

References 91 publications

Hierarchical Computational Modeling and Dynamic Network Analysis of Allosteric Regulation in the SARS-CoV-2 Spike Omicron Trimer Structures: Omicron Mutations Cooperate to Allosterically Control Balance of Protein Stability and Conformational Adaptability

Hierarchical Computational Modeling and Dynamic Network Analysis of Allosteric Regulation in the SARS-CoV-2 Spike Omicron Trimer Structures: Omicron Mutations Cooperate to Allosterically Control Balance of Protein Stability and Conformational Adaptability

An Investigation of the YidC-Mediated Membrane Insertion of Pf3 Coat Protein Using Molecular Dynamics Simulations

Deciphering the Inter-domain Decoupling in the Gram-negative Bacterial Membrane Insertase

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