scholarly journals A Multiscale Coarse-grained Model of the SARS-CoV-2 Virion

2020 ◽  
Author(s):  
Alvin Yu ◽  
Alexander J. Pak ◽  
Peng He ◽  
Viviana Monje-Galvan ◽  
Lorenzo Casalino ◽  
...  
Keyword(s):  
Large Scale ◽  
Molecular Model ◽  
Structural Data ◽  
Coarse Grained ◽  
Atomistic Simulations ◽  
Current Status ◽  
Multiscale Approach ◽  
X Ray Crystallography ◽  
Coarse Grained Model ◽  
Viral Particles

AbstractThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the COVID-19 pandemic. Computer simulations of complete viral particles can provide theoretical insights into large-scale viral processes including assembly, budding, egress, entry, and fusion. Detailed atomistic simulations, however, are constrained to shorter timescales and require billion-atom simulations for these processes. Here, we report the current status and on-going development of a largely “bottom-up” coarse-grained (CG) model of the SARS-CoV-2 virion. Structural data from a combination of cryo-electron microscopy (cryo-EM), x-ray crystallography, and computational predictions were used to build molecular models of structural SARS-CoV-2 proteins, which were then assembled into a complete virion model. We describe how CG molecular interactions can be derived from all-atom simulations, how viral behavior difficult to capture in atomistic simulations can be incorporated into the CG models, and how the CG models can be iteratively improved as new data becomes publicly available. Our initial CG model and the detailed methods presented are intended to serve as a resource for researchers working on COVID-19 who are interested in performing multiscale simulations of the SARS-CoV-2 virion.Significance StatementThis study reports the construction of a molecular model for the SARS-CoV-2 virion and details our multiscale approach towards model refinement. The resulting model and methods can be applied to and enable the simulation of SARS-CoV-2 virions.

Symmetry-adapted digital modeling III. Coarse-grained icosahedral viruses

2016 ◽  
Vol 72 (3) ◽  
pp. 324-337 ◽  
Author(s):  
A. Janner
Keyword(s):  
Lattice Point ◽  
Three Dimensional ◽  
Structural Data ◽  
Data Bank ◽  
Coarse Grained ◽  
Large Set ◽  
Fine Grained ◽  
Coarse Grained Model ◽  
Digital Modeling ◽  
Icosahedral Viruses

Considered is the coarse-grained modeling of icosahedral viruses in terms of a three-dimensional lattice (the digital modeling lattice) selected among the projected points in space of a six-dimensional icosahedral lattice. Backbone atomic positions (Cα's for the residues of the capsid and phosphorus atoms P for the genome nucleotides) are then indexed by their nearest lattice point. This leads to a fine-grained lattice point characterization of the full viral chains in the backbone approximation (denoted as digital modeling). Coarse-grained models then follow by a proper selection of the indexed backbone positions, where for each chain one can choose the desired coarseness. This approach is applied to three viruses, the Satellite tobacco mosaic virus, the bacteriophage MS2 and the Pariacoto virus, on the basis of structural data from the Brookhaven Protein Data Bank. In each case the various stages of the procedure are illustrated for a given coarse-grained model and the corresponding indexed positions are listed. Alternative coarse-grained models have been derived and compared. Comments on related results and approaches, found among the very large set of publications in this field, conclude this article.

scholarly journals Identifying dynamic, partially occupied residues using anomalous scattering

2019 ◽  
Author(s):  
Serena Rocchio ◽  
Ramona Duman ◽  
Kamel El Omari ◽  
Vitaliy Mykhaylyk ◽  
Zhen Yan ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Large Scale ◽  
Structural Changes ◽  
Structural Data ◽  
Anomalous Scattering ◽  
Long Wavelength ◽  
X Ray Crystallography ◽  
Structural Ensembles ◽  
Analysis Strategy ◽  
Chain Conformations

AbstractX-ray crystallography is generally used to take single snapshots of a protein’s conformation. The important but difficult task of characterizing structural ensembles in crystals is typically limited to small conformational changes, such as multiple side-chain conformations. A crystallographic method was recently introduced that utilizes Residual Anomalous and Electron Density (READ) to characterize structural ensembles encompassing large-scale structural changes. Key to this method is an ability to accurately measure anomalous signals and distinguish them from noise or other anomalous scatterers. This report presents an optimized data collection and analysis strategy for partially occupied iodine anomalous signals. Using the long wavelength-optimized beamline I23 at Diamond Light Source, the ability to accurately distinguish the positions of anomalous scatterers with as low as ~12% occupancy is demonstrated. The number and position of these anomalous scatterers are consistent with previous biophysical, kinetic and structural data that suggest the protein Im7 binds to the chaperone Spy in multiple partially occupied conformations. This study shows that a long-wavelength beamline results in easily validated anomalous signals that are strong enough to be used to detect and characterize highly dynamic sections of crystal structures.SynopsisStructural studies on partially occupied, dynamic protein systems by crystallography are difficult. We present methods here for detecting these states in crystals.

scholarly journals Single-molecule biophysics experiments in silico: Towards a physical model of a replisome

2021 ◽  
Author(s):  
Christopher Maffeo ◽  
Han-Yi Chou ◽  
Aleksei Aksimentiev
Keyword(s):  
Single Molecule ◽  
In Silico ◽  
Computational Models ◽  
Coarse Grained ◽  
Atomistic Simulations ◽  
Test Bed ◽  
Computing Power ◽  
Coarse Grained Model ◽  
Biomolecular Dynamics ◽  
Single Molecule Studies

AbstractThe interpretation of single-molecule experiments is frequently aided by computational modeling of biomolecular dynamics. The growth of computing power and ongoing validation of computational models suggest that it soon may be possible to replace some experiments out-right with computational mimics. Here we offer a blueprint for performing single-molecule studies in silico using a DNA binding protein as a test bed. We demonstrate how atomistic simulations, typically limited to sub-millisecond durations and zeptoliter volumes, can guide development of a coarse-grained model for use in simulations that mimic experimental assays. We show that, after initially correcting excess attraction between the DNA and protein, qualitative consistency between several experiments and their computational equivalents is achieved, while additionally providing a detailed portrait of the underlying mechanics. Finally the model is used to simulate the trombone loop of a replication fork, a large complex of proteins and DNA.

scholarly journals Quantitative analysis of membrane-mediated interactions and aggregation of flexible peripheral proteins orchestrating large-scale membrane remodeling

2021 ◽  
Author(s):  
Mohsen Sadeghi ◽  
Frank Noe
Keyword(s):  
Protein Interactions ◽  
Large Scale ◽  
Effective Interaction ◽  
Bilayer Membrane ◽  
Coarse Grained ◽  
Membrane Remodeling ◽  
Coarse Grained Model ◽  
Sequence Of Events ◽  
Peripheral Proteins ◽  
The Stability

Shaping and remodeling of biomembranes is essential for cellular trafficking, with membrane-binding peripheral proteins playing the key role in it. Significant membrane remodeling as in endo- and exocytosis is often due to clusters or aggregates of many proteins whose interactions may be direct or mediated via the membrane. While computer simulation could be an important tool to disentangle these interactions and understand what drives cooperative protein interactions in membrane remodeling, this has so far been extremely challenging: protein-membrane systems involve time- and lengthscales that make detailed atomistic simulations impractical, while most coarse-grained models lack the degree of detail needed to resolve the dynamics and physical effect of protein and membrane flexibility. Here, we develop a coarse-grained model of the bilayer membrane bestrewed with rotationally-symmetric flexible membrane-bound proteins. We show how this model can be parameterized based on local curvatures, protein flexibility, and the in-plane dynamics of proteins. We measure the effective interaction potential for the membrane-mediated interactions between peripheral proteins. Furthermore, we investigate the kinetics, equilibrium distributions, and the free energy landscape governing the formation and break-up of protein clusters on the surface of the membrane. We demonstrate how the flexibility of the protein plays a deciding role in highly selective macroscopic aggregation behavior. Finally, we present large-scale simulations of membrane tubulation, and discuss the sequence of events and the stability of intermediates.

Developing Coarse-Grained Force Fields of Poly (methylmethacrylate-b-2-vinylpyridine) from Atomistic Simulation

2012 ◽  
Vol 562-564 ◽  
pp. 123-128 ◽  
Author(s):  
Bo Du ◽  
Zi Lu Wang ◽  
Xue Hao He
Keyword(s):  
Mechanical Properties ◽  
Force Field ◽  
Self Assembly ◽  
Atomistic Simulation ◽  
Polymer Melts ◽  
Coarse Grained ◽  
Atomistic Simulations ◽  
Inversion Method ◽  
Coarse Grained Model ◽  
Vinyl Pyridine

A coarse-grained force field for poly (methylmethacrylate-b-2-vinyl pyridine) is developed based on the Iterative Boltzmann Inversion method. The proposed coarse-grained model, successfully reproduced the properties of the polymer melts obtained from atomistic simulations, may provide an efficient way to study their mechanical properties and self-assembly behaviors.

scholarly journals Accurate sequence-dependent coarse-grained model for conformational and elastic properties of double-stranded DNA

2021 ◽  
Author(s):  
Salvatore Assenza ◽  
Rubén Pérez
Keyword(s):  
Persistence Length ◽  
Independent Set ◽  
Single Step ◽  
Coarse Grained ◽  
Atomistic Simulations ◽  
Sequence Dependence ◽  
Cellular Processes ◽  
Coarse Grained Model ◽  
Double Stranded Dna ◽  
Sequence Dependent

AbstractWe introduce MADna, a sequence-dependent coarse-grained model of double-stranded DNA (dsDNA), where each nucleotide is described by three beads localized at the sugar and base moieties, and at the phosphate group. The sequence dependence is included by considering a step-dependent parameterization of the bonded interactions, which are tuned in order to reproduce the values of key observables obtained from exhaustive atomistic simulations from literature. The predictions of the model are benchmarked against an independent set of all-atom simulations, showing that it captures with high fidelity the sequence dependence of conformational and elastic features beyond the single step considered in its formulation. A remarkably good agreement with experiments is found for both sequence-averaged and sequence-dependent conformational and elastic features, including the stretching and torsion moduli, the twist-stretch and twist-bend couplings, the persistence length and the helical pitch. Overall, for the inspected quantities, the model has a precision comparable to atomistic simulations, hence providing a reliable coarse-grained description for the rationalization of singlemolecule experiments and the study of cellular processes involving dsDNA. Owing to the simplicity of its formulation, MADna can be straightforwardly included in common simulation engines.

scholarly journals Cover art

2016 ◽  
Vol 85 (1) ◽  
Author(s):  
Rakesh Gudimella
Keyword(s):  
Large Scale ◽  
Molecular Model ◽  
Essential Medicines ◽  
Chemical Formula ◽  
X Ray Diffraction ◽  
X Ray ◽  
X Ray Crystallography ◽  
Chemical Structures ◽  
Diffraction Patterns ◽  
Cover Art

Cover art by Rakesh Gudimella. In 1964, Dorothy Hodgkin won the Nobel Prize for the discovery of the structure of penicillin using the emerging technique of x-ray crystallography. The original x-ray diffraction patterns and the subsequent molecular model she created is shown in the foreground. Although the chemical formula of penicillin was known, its structure was not, making it difficult to produce on a large scale. Her discovery set us on the path to understanding antibiotic mechanisms and opened the door for the synthesis of cephalosporins and other important medications. The background shows the chemical structures of several lifesaving and influential drugs on the WHO List of Essential Medicines.

scholarly journals Chromosome compartmentalization replacement during stem cell differentiation

2018 ◽  
Author(s):  
Y.A. Eidelman ◽  
S.V. Slanina ◽  
V.S. Pyatenko ◽  
S.G. Andreev
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Large Scale ◽  
3D Structure ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Coarse Grained ◽  
Interphase Chromosome ◽  
Coarse Grained Model ◽  
Differentiated Cells

ABSTRACTIn this paper, changes in a large-scale 3D structure of chromosomes during stem cell differentiation is studied. The polymer coarse-grained model of a human interphase chromosome is introduced which reproduces the experimental Hi-C contact maps in chromosomes 12, 17 for both embryonic stem and differentiated cells with high accuracy. Model based analysis of Hi-C data suggests a mechanism of establishment of preferential long-range chromosomal contacts and compartmentalization replacement during cell stem differentiation. The model provides the conceptual basis for integration of data on the dynamics of chromatin interactions, the 3D structure of chromosomes and gene expression during stem cell differentiation or reprogramming.

scholarly journals Quantitative analysis of membrane-mediated interactions and aggregation of flexible peripheral proteins orchestrating large-scale membrane remodeling

2021 ◽  
Author(s):  
Mohsen Sadeghi ◽  
Frank Noé
Keyword(s):  
Protein Interactions ◽  
Large Scale ◽  
Effective Interaction ◽  
Bilayer Membrane ◽  
Coarse Grained ◽  
Membrane Remodeling ◽  
Coarse Grained Model ◽  
Sequence Of Events ◽  
Peripheral Proteins ◽  
The Stability

Abstract Shaping and remodeling of biomembranes is essential for cellular trafficking, with membrane-binding peripheral proteins playing the key role in it. Significant membrane remodeling as in endo- and exocytosis is often due to clusters or aggregates of many proteins whose interactions may be direct or mediated via the membrane. While computer simulation could be an important tool to disentangle these interactions and understand what drives cooperative protein interactions in membrane remodeling, this has so far been extremely challenging: protein-membrane systems involve time- and lengthscales that make detailed atomistic simulations impractical, while most coarse-grained models lack the degree of detail needed to resolve the dynamics and physical effect of protein and membrane flexibility. Here, we develop a coarse-grained model of the bilayer membrane bestrewed with rotationally-symmetric flexible membrane-bound proteins. We show how this model can be parameterized based on local curvatures, protein flexibility, and the in-plane dynamics of proteins. We measure the effective interaction potential for the membrane-mediated interactions between peripheral proteins. Furthermore, we investigate the kinetics, equilibrium distributions, and the free energy landscape governing the formation and break-up of protein clusters on the surface of the membrane. We demonstrate how the flexibility of the protein plays a deciding role in highly selective macroscopic aggregation behavior. Finally, we present large-scale simulations of membrane tubulation, and discuss the sequence of events and the stability of intermediates.

scholarly journals Coarse graining from variationally enhanced sampling applied to the Ginzburg–Landau model

2017 ◽  
Vol 114 (13) ◽  
pp. 3370-3374 ◽  
Author(s):  
Michele Invernizzi ◽  
Omar Valsson ◽  
Michele Parrinello
Keyword(s):  
Critical Point ◽  
Sampling Method ◽  
Coarse Graining ◽  
Coarse Grained ◽  
Atomistic Simulations ◽  
Enhanced Sampling ◽  
Ginzburg Landau ◽  
Coarse Grained Model ◽  
Unique Approach ◽  
Physical Features

A powerful way to deal with a complex system is to build a coarse-grained model capable of catching its main physical features, while being computationally affordable. Inevitably, such coarse-grained models introduce a set of phenomenological parameters, which are often not easily deducible from the underlying atomistic system. We present a unique approach to the calculation of these parameters, based on the recently introduced variationally enhanced sampling method. It allows us to obtain the parameters from atomistic simulations, providing thus a direct connection between the microscopic and the mesoscopic scale. The coarse-grained model we consider is that of Ginzburg–Landau, valid around a second-order critical point. In particular, we use it to describe a Lennard–Jones fluid in the region close to the liquid–vapor critical point. The procedure is general and can be adapted to other coarse-grained models.

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