A Multiscale Computational Model for Simulating the Kinetics of Protein Complex Assembly

Chen, Jiawen; Wu, Yinghao

doi:10.1007/978-1-4939-7759-8_26

Cited by 6 publications

(5 citation statements)

References 46 publications

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“…Members of Rho GTPase family, including Rho, Rac, are believed to play pivotal roles during the maturation process of the intercellular junction. Rac, an initiator of the actin branching network and lamellipodia, is upregulated rapidly once the cells touch each other, and is blocked if the cadherin binding sites are inhibited [11][12][13][14][15]. On the other hand, Rho, a regulator of myosin, which contracts and stiffens the actin network, is down-regulated by cadherin ligation through the cross-talk between Rho and Rac [16].…”

Section: Introductionmentioning

confidence: 99%

Cortical tension initiates the positive feedback loop between cadherin and F-actin

Yu¹,

Holmes²,

Thiéry³

et al. 2022

Biophysical Journal

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Section: Introductionmentioning

confidence: 99%

Cortical tension initiates the positive feedback loop between cadherin and F-actin

Yu¹,

Holmes²,

Thiéry³

et al. 2022

Biophysical Journal

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“…The detailed analysis of how different linkers can regulate the binding between biologics and their corresponding receptors on T cell surfaces is beyond the scope of this work. Such research will be conducted in a follow‐up study that integrates the MD simulations into our previously developed multiscale modeling framework 54,55 …”

Section: Concluding Discussionmentioning

confidence: 99%

Characterizing the function of domain linkers in regulating the dynamics of multi‐domain fusion proteins by microsecond molecular dynamics simulations and artificial intelligence

Wang

2021

Proteins

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Multi‐domain proteins are not only formed through natural evolution but can also be generated by recombinant DNA technology. Because many fusion proteins can enhance the selectivity of cell targeting, these artificially produced molecules, called multi‐specific biologics, are promising drug candidates, especially for immunotherapy. Moreover, the rational design of domain linkers in fusion proteins is becoming an essential step toward a quantitative understanding of the dynamics in these biopharmaceutics. We developed a computational framework to characterize the impacts of peptide linkers on the dynamics of multi‐specific biologics. Specifically, we first constructed a benchmark containing six types of linkers that represent various lengths and degrees of flexibility and used them to connect two natural proteins as a test system. We then projected the microsecond dynamics of these proteins generated from Anton onto a coarse‐grained conformational space. We further analyzed the similarity of dynamics among different proteins in this low‐dimensional space by a neural‐network‐based classification model. Finally, we applied hierarchical clustering to place linkers into different subgroups based on the classification results. The clustering results suggest that the length of linkers, which is used to spatially separate different functional modules, plays the most important role in regulating the dynamics of this fusion protein. Given the same number of amino acids, linker flexibility functions as a regulator of protein dynamics. In summary, we illustrated that a new computational strategy can be used to study the dynamics of multi‐domain fusion proteins by a combination of long timescale molecular dynamics simulation, coarse‐grained feature extraction, and artificial intelligence.

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“…After the initial setup, simulations are followed by a diffusion–reaction algorithm . The algorithm details were delineated in our previous works. , Briefly, each simulation step consists of two independent scenarios of movements. The first scenario is called diffusion, in which dimers are randomly diffused along their three translational and three rotational degrees of freedom.…”

Section: Methodsmentioning

confidence: 99%

“…Consequently, the values of the association rate r on and the effective distance of association d on are derived from the statistical analysis of these trajectories, as described in our previous study . These effective rate and distance are integrated in the rigid body-based model ,, to simulate capsid assembly. To connect residue-based and rigid body-based simulations with the same timescale, the maximal time duration to terminate each trajectory of residue-based simulations is fixed to Δ t RB , which is the length of time step in the rigid body simulation.…”

Section: Methodsmentioning

confidence: 99%

A Multiscale Model for the Self-Assembly of Coat Proteins in Bacteriophage MS2

Wang

Zhang

2019

J. Chem. Inf. Model.

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The self-assembly of viral capsids is an essential step to the formation of infectious viruses. Elucidating the kinetic mechanisms of how a capsid or virus-like particle assembles could advance our knowledge about the viral lifecycle, as well as the general principles in self-assembly of biomaterials. However, current understanding of capsid assembly remains incomplete for many viruses due to the fact that the transient intermediates along the assembling pathways are experimentally difficult to be detected. In this paper, we constructed a new multiscale computational framework to simulate the self-assembly of virus like particles. We applied our method to the coat proteins of Bacteriophage MS2 as a specific model system. This virus-like particle of Bacteriophage MS2 has a unique feature that its 90 sequence-identical dimers can be classified into two structurally various groups: one is the symmetric CC dimer; the other is the asymmetric AB dimer. The homotypic interactions between AB dimers result in a 5-fold symmetric contact, while the heterotypic interactions between AB and CC dimers result in 6-fold symmetric contact. We found that the assembly can be described as a physical process of phase transition that is regulated by various factors such as concentration and specific stoichiometry between AB and CC dimers. Our simulations also demonstrate that heterotypic and homotypic interfaces play distinctive roles in modulating the assembling kinetics. The interaction between AB and CC dimers is much more dynamic than the interaction between two AB dimers. We therefore suggest that the alternate growth of viral capsid through the heterotypic dimer interactions dominates the assembling pathways. This is, to the best of our knowledge, the first multiscale model to simulate the assembling process of coat proteins in Bacteriophage MS2. The generality of this approach opens the door to its further applications in assembly of other viral capsids, virus-like particles and novel drug delivery systems.

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A Multiscale Computational Model for Simulating the Kinetics of Protein Complex Assembly

Cited by 6 publications

References 46 publications

Cortical tension initiates the positive feedback loop between cadherin and F-actin

Cortical tension initiates the positive feedback loop between cadherin and F-actin

Characterizing the function of domain linkers in regulating the dynamics of multi‐domain fusion proteins by microsecond molecular dynamics simulations and artificial intelligence

A Multiscale Model for the Self-Assembly of Coat Proteins in Bacteriophage MS2

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