Activation Pathways and Free Energy Landscapes of the SARS-CoV-2 Spike Protein

Wu, Yichao; Qian, Ruixin; Yang, Yan; Sheng, Yinghong; Li, Wenfei; Wang, Wei

doi:10.1021/acsomega.1c03384

Cited by 8 publications

(10 citation statements)

References 56 publications

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“…2 c, S 1 a). This finding is consistent with multiple computational studies using various enhanced sampling methods, which also concluded that the down state is the more probable conformation 33 , 34 , 39 , 40 . The differences between the two end-state energy wells do not end with their depth but also their breadth.…”

Section: Resultssupporting

confidence: 91%

SARS-CoV-2 spike opening dynamics and energetics reveal the individual roles of glycans and their collective impact

et al. 2022

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The trimeric spike (S) glycoprotein, which protrudes from the SARS-CoV-2 viral envelope, binds to human ACE2, initiated by at least one protomer’s receptor binding domain (RBD) switching from a "down” (closed) to an "up” (open) state. Here, we used large-scale molecular dynamics simulations and two-dimensional replica exchange umbrella sampling calculations with more than a thousand windows and an aggregate total of 160 μs of simulation to investigate this transition with and without glycans. We find that the glycosylated spike has a higher barrier to opening and also energetically favors the down state over the up state. Analysis of the S-protein opening pathway reveals that glycans at N165 and N122 interfere with hydrogen bonds between the RBD and the N-terminal domain in the up state, while glycans at N165 and N343 can stabilize both the down and up states. Finally, we estimate how epitope exposure for several known antibodies changes along the opening path. We find that the BD-368-2 antibody’s epitope is continuously exposed, explaining its high efficacy.

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Section: Resultssupporting

confidence: 91%

SARS-CoV-2 spike opening dynamics and energetics reveal the individual roles of glycans and their collective impact

et al. 2022

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“…2c, S1a). This finding is consistent with multiple computational studies using various enhanced sampling methods, which also concluded that the down state is the more probable conformation 33,34,39,40 . The differences between the two end-state energy wells does not end with their depth but also their breadth.…”

Section: Resultssupporting

confidence: 91%

SARS-CoV-2 spike opening dynamics and energetics reveal the individual roles of glycans and their collective impact

Pang

Acharya

Lynch

et al. 2021

Preprint

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The trimeric spike (S) glycoprotein, which protrudes from the SARS-CoV-2 viral envelope, is responsible for binding to human ACE2 receptors. The binding process is initiated when the receptor binding domain (RBD) of at least one protomer switches from a "down" (closed) to an "up" (open) state. Here, we used molecular dynamics simulations and two-dimensional replica exchange umbrella sampling calculations to investigate the transition between the two S-protein conformations with and without glycosylation. We show that the glycosylated spike has a higher barrier to opening than the non-glycosylated one with comparable populations of the down and up states. In contrast, we observed that the up conformation is favored without glycans. Analysis of the S-protein opening pathway reveals that glycans at N165 and N122 interfere with hydrogen bonds between the RBD and the N-terminal domain in the up state. We also identify roles for glycans at N165 and N343 in stabilizing the down and up states. Finally we estimate how epitope exposure for several known antibodies changes along the opening path. We find that the epitope of the BD-368-2 antibody remains exposed irrespective of the S-protein conformation, explaining the high efficacy of this antibody.

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“…With protein structure we obtained from the above methods, MD simulation can be performed to study conformational change, protein–protein interactions, and ligand binding (Nguyen et al, 2016; Rifai et al, 2019; Wise‐Scira et al, 2013; Wu, Qian, et al, 2021). Traditional all‐atom MD simulations can be performed with Amber (Case et al, 2021), GROMACS (Van Der Spoel et al, 2005), etc.…”

Section: Force Fieldmentioning

confidence: 99%

Application of molecular dynamics simulation in biomedicine

et al. 2022

Chem Biol Drug Des

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Molecular dynamics (MD) simulation has been widely used in the field of biomedicine to study the conformational transition of proteins caused by mutation or ligand binding/unbinding. It provides some perspectives those are difficult to find in traditional biochemical or pathological experiments, for example, detailed effects of mutations on protein structure and protein–protein/ligand interaction at the atomic level. In this review, a broad overview on conformation changes and drug discovery by MD simulation is given. We first discuss the preparation of protein structure for MD simulation, which is a key step that determines the accuracy of the simulation. Then, we summarize the applications of commonly used force fields and MD simulations in scientific research. Finally, enhanced sampling methods and common applications of these methods are introduced. In brief, MD simulation is a powerful tool and it can be used to guide experimental study. The combination of MD simulation and experimental techniques is an a priori means to solve the biomedical problems and give a deep understanding on the relationship between protein structure and function.

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Activation Pathways and Free Energy Landscapes of the SARS-CoV-2 Spike Protein

Cited by 8 publications

References 56 publications

SARS-CoV-2 spike opening dynamics and energetics reveal the individual roles of glycans and their collective impact

SARS-CoV-2 spike opening dynamics and energetics reveal the individual roles of glycans and their collective impact

SARS-CoV-2 spike opening dynamics and energetics reveal the individual roles of glycans and their collective impact

Application of molecular dynamics simulation in biomedicine

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