Large-scale simulations of nucleoprotein complexes: ribosomes, nucleosomes, chromatin, chromosomes and CRISPR

Sanbonmatsu, Karissa Y.

doi:10.1016/j.sbi.2019.03.004

Cited by 21 publications

(13 citation statements)

References 139 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Yet, detailed 3D structures can serve as an important basis or complement for more direct studies of the underlying kinetics. Coarse-grained and atomistic molecular dynamics simulations take 3D structures as an input to model the thermodynamic and kinetic properties of the ribosome [ 86 , 87 ]. On the experimental side, understanding the 3D structure has been useful to guide and interpret single molecule fluorescence imaging experiments which offer time series data of the ribosome [ 78 , 88 ].…”

Section: The Multiple Sources Of Heterogeneity In Ribosome Structumentioning

confidence: 99%

Structural Heterogeneities of the Ribosome: New Frontiers and Opportunities for Cryo-EM

Poitevin

Kushner

et al. 2020

Molecules

View full text Add to dashboard Cite

The extent of ribosomal heterogeneity has caught increasing interest over the past few years, as recent studies have highlighted the presence of structural variations of the ribosome. More precisely, the heterogeneity of the ribosome covers multiple scales, including the dynamical aspects of ribosomal motion at the single particle level, specialization at the cellular and subcellular scale, or evolutionary differences across species. Upon solving the ribosome atomic structure at medium to high resolution, cryogenic electron microscopy (cryo-EM) has enabled investigating all these forms of heterogeneity. In this review, we present some recent advances in quantifying ribosome heterogeneity, with a focus on the conformational and evolutionary variations of the ribosome and their functional implications. These efforts highlight the need for new computational methods and comparative tools, to comprehensively model the continuous conformational transition pathways of the ribosome, as well as its evolution. While developing these methods presents some important challenges, it also provides an opportunity to extend our interpretation and usage of cryo-EM data, which would more generally benefit the study of molecular dynamics and evolution of proteins and other complexes.

show abstract

Section: The Multiple Sources Of Heterogeneity In Ribosome Structumentioning

confidence: 99%

Structural Heterogeneities of the Ribosome: New Frontiers and Opportunities for Cryo-EM

Poitevin

Kushner

et al. 2020

Molecules

View full text Add to dashboard Cite

show abstract

“…Modeling and simulation provide an attractive alternative approach to studying the structure, dynamics, and mechanics of multi-protein arrays (113,(136)(137)(138), including of cadherins complexes. Indeed, some classical cadherin-based junctions have been simulated previously and were modeled as either coarsegrained (139), rigid-body (56,140), or all-atom (42) systems including only the adhesive cadherin ectodomains.…”

Section: Discussionmentioning

confidence: 99%

Collective Mechanical Responses of Cadherin-Based Adhesive Junctions as Predicted by Simulations

Neel

Nisler

Walujkar

et al. 2021

Preprint

View full text Add to dashboard Cite

Cadherin-based adherens junctions and desmosomes help stabilize cell-cell contacts with additional function in mechano-signaling, while clustered protocadherin junctions are responsible for directing neuronal circuits assembly. Structural models for adherens junctions formed by epithelial cadherin (CDH1) proteins indicate that their long, curved ectodomains arrange to form a periodic, two-dimensional lattice stabilized by tip-to-tip trans interactions (across junction) and lateral cis contacts. Less is known about the exact architecture of desmosomes, but desmoglein (DSG) and desmocollin (DSC) cadherin proteins are also thought to form ordered junctions. In contrast, clustered protocadherin (PCDH) based cell-cell contacts in neuronal tissues are thought to be responsible for self-recognition and avoidance, and structural models for clustered PCDH junctions show a linear arrangement in which their long and straight ectodomains form antiparallel overlapped trans complexes. Here we report all-atom molecular dynamics simulations testing the mechanics of minimalistic adhesive junctions formed by CDH1, DSG2 coupled to DSC1, and PCDHγB4, with systems encompassing up to 3.7 million atoms. Simulations generally predict a favored shearing pathway for the adherens junction model and a two-phased elastic response to tensile forces for the adhesive adherens junction and the desmosome models. Complexes within these junctions first unbend at low tensile force and then become stiff to unbind without unfolding. However, cis interactions in both the CDH1 and DSG2-DSC1 systems dictate varied mechanical responses of individual dimers within the junctions. Conversely, the clustered protocadherin PCDHγB4 junction lacks a distinct two-phased elastic response. Instead, applied tensile force strains trans interactions directly as there is little unbending of monomers within the junction. Transient intermediates, influenced by new cis interactions, are observed after the main rupture event. We suggest that these collective, complex mechanical responses mediated by cis contacts facilitate distinct functions in robust cell-cell adhesion for classical cadherins and in self-avoidance signaling for clustered PCDHs.

show abstract

“…Computational simulation studies have been used to bring out the detailed energetics and intermolecular interactions involved in various steps in protein synthesis [46,47,48,49,50,51,52].…”

Section: Discussionmentioning

confidence: 99%

“…Computational simulation studies have been used to bring out the detailed energetics and intermolecular interactions involved in various steps in protein synthesis [46,47,48,49,50,51,52]. Recently, MD simulations studies were done to study codon selection in translation initiation in the closed conformation of the 48S PIC [16,17].…”

Section: Discussionmentioning

confidence: 99%

Selection of start codon during mRNA scanning in eukaryotic translation initiation

Basu

Gorai

Chandran

et al. 2020

Preprint

View full text Add to dashboard Cite

During translational initiation in eukaryotes, the small ribosomal subunit forms a 48S preinitiation complex (PIC) with initiation factors. The 48S PIC binds to the 5' end of mRNA and inspects long untranslated region (UTR) for the presence of the start codon (AUG). Accurate and high speed of scanning 5' UTR and subsequent selection of the correct start codon are crucial for protein synthesis. However, the conformational state of 48S PIC required for inspecting every codon is not clearly understood. Whether the scanning or open conformation of 48S PIC can accurately select the cognate start codon over near/non-cognate codons, or this discrimination is carried out only in the scanning-arrested or closed conformation of 48S PIC. Here, using atomistic molecular dynamics (MD) simulations and free energy calculations, we show that the scanning conformation of 48S PIC can reject all but 4 of the 63 non-AUG codons. Among nine near-cognate codons with a single mismatch, only codons with a first position mismatch (GUG, CUG and UUG) or a pyrimidine mismatch at the second position (ACG) are not discriminated by scanning state of 48S PIC. In contrast, any mismatch in the third position is rejected. Simulations runs in absence of one or more eukaryotic initiation factors (eIF1, eIF1+eIF1A, eIF2ɑ or eIF2β) from the system show critical role of eIF1 and eIF2ɑ in start codon selection. The structural analysis indicates that tRNAi dynamics at the widened P site of 48S open state drives codon selection. Further, a stable codon: anticodon interaction prepares the PIC to transit to the closed state. Overall, we provide insights into the selection of start codon during scanning and how the open conformation of 48S PIC can scan long 5' UTRs with accuracy and high speed without the requirement of sampling the closed state for every codon.

show abstract

Large-scale simulations of nucleoprotein complexes: ribosomes, nucleosomes, chromatin, chromosomes and CRISPR

Cited by 21 publications

References 139 publications

Structural Heterogeneities of the Ribosome: New Frontiers and Opportunities for Cryo-EM

Structural Heterogeneities of the Ribosome: New Frontiers and Opportunities for Cryo-EM

Collective Mechanical Responses of Cadherin-Based Adhesive Junctions as Predicted by Simulations

Selection of start codon during mRNA scanning in eukaryotic translation initiation

Contact Info

Product

Resources

About