scholarly journals Molecular architecture of SARS-CoV-2 envelope by integrative modeling

2021 ◽  
Author(s):  
Weria Pezeshkian ◽  
Fabian Grünewald ◽  
Oleksandr Narykov ◽  
Senbao Lu ◽  
Tsjerk A Wassenaar ◽  
...  

AbstractDespite tremendous efforts by research community during the COVID-19 pandemic, the exact structure of SARS-CoV-2 and related betacoronaviruses remains elusive. Here, we developed and applied an integrative multi-scale computational approach to model the envelope structure of SARS-CoV-2, focusing on studying the dynamic nature and molecular interactions of its most abundant, but largely understudied, M (membrane) protein. The molecular dynamics simulations allowed us to test the envelop stability under different configurations and revealed that M dimers agglomerated into large, filament-like, macromolecular assemblies with distinct molecular patterns formed by M’s transmembrane and intra-virion (endo) domains. These results were in agreement with the experimental data, demonstrating a generic and versatile integrative approach to model the structure of a virus de novo, providing insights into critical roles of structural proteins in the viral assembly and integration, and proposing new targets for the antiviral therapies.

2019 ◽  
Vol 28 (15) ◽  
pp. 2501-2513 ◽  
Author(s):  
Jacqueline A C Goos ◽  
Walter K Vogel ◽  
Hana Mlcochova ◽  
Christopher J Millard ◽  
Elahe Esfandiari ◽  
...  

Abstract Craniosynostosis, the premature ossification of cranial sutures, is a developmental disorder of the skull vault, occurring in approximately 1 in 2250 births. The causes are heterogeneous, with a monogenic basis identified in ~25% of patients. Using whole-genome sequencing, we identified a novel, de novo variant in BCL11B, c.7C>A, encoding an R3S substitution (p.R3S), in a male patient with coronal suture synostosis. BCL11B is a transcription factor that interacts directly with the nucleosome remodelling and deacetylation complex (NuRD) and polycomb-related complex 2 (PRC2) through the invariant proteins RBBP4 and RBBP7. The p.R3S substitution occurs within a conserved amino-terminal motif (RRKQxxP) of BCL11B and reduces interaction with both transcriptional complexes. Equilibrium binding studies and molecular dynamics simulations show that the p.R3S substitution disrupts ionic coordination between BCL11B and the RBBP4–MTA1 complex, a subassembly of the NuRD complex, and increases the conformational flexibility of Arg-4, Lys-5 and Gln-6 of BCL11B. These alterations collectively reduce the affinity of BCL11B p.R3S for the RBBP4–MTA1 complex by nearly an order of magnitude. We generated a mouse model of the BCL11B p.R3S substitution using a CRISPR-Cas9-based approach, and we report herein that these mice exhibit craniosynostosis of the coronal suture, as well as other cranial sutures. This finding provides strong evidence that the BCL11B p.R3S substitution is causally associated with craniosynostosis and confirms an important role for BCL11B in the maintenance of cranial suture patency.


2020 ◽  
Vol 21 (12) ◽  
pp. 4447
Author(s):  
Pedro A. Lazo ◽  
Juan L. García ◽  
Paulino Gómez-Puertas ◽  
Íñigo Marcos-Alcalde ◽  
Cesar Arjona ◽  
...  

Complex neurodevelopmental syndromes frequently have an unknown etiology, in which genetic factors play a pathogenic role. This study utilizes whole-exome sequencing (WES) to examine four members of a family with a son presenting, since birth, with epileptic-like crises, combined with cerebral palsy, severe neuromotor and developmental delay, dystonic tetraparexia, axonal motor affectation, and hyper-excitability of unknown origin. The WES study detected within the patient a de novo heterozygous in-frame duplication of thirty-six nucleotides within exon 7 of the human KCNQ2 gene. This insertion duplicates the first twelve amino acids of the calmodulin binding site I. Molecular dynamics simulations of this KCNQ2 peptide duplication, modelled on the 3D structure of the KCNQ2 protein, suggest that the duplication may lead to the dysregulation of calcium inhibition of this protein function.


2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Leandro de Araújo Lima ◽  
Ana Cecília Feio-dos-Santos ◽  
Sintia Iole Belangero ◽  
Ary Gadelha ◽  
Rodrigo Affonseca Bressan ◽  
...  

Abstract Many studies have attempted to investigate the genetic susceptibility of Attention-Deficit/Hyperactivity Disorder (ADHD), but without much success. The present study aimed to analyze both single-nucleotide and copy-number variants contributing to the genetic architecture of ADHD. We generated exome data from 30 Brazilian trios with sporadic ADHD. We also analyzed a Brazilian sample of 503 children/adolescent controls from a High Risk Cohort Study for the Development of Childhood Psychiatric Disorders, and also previously published results of five CNV studies and one GWAS meta-analysis of ADHD involving children/adolescents. The results from the Brazilian trios showed that cases with de novo SNVs tend not to have de novo CNVs and vice-versa. Although the sample size is small, we could also see that various comorbidities are more frequent in cases with only inherited variants. Moreover, using only genes expressed in brain, we constructed two “in silico” protein-protein interaction networks, one with genes from any analysis, and other with genes with hits in two analyses. Topological and functional analyses of genes in this network uncovered genes related to synapse, cell adhesion, glutamatergic and serotoninergic pathways, both confirming findings of previous studies and capturing new genes and genetic variants in these pathways.


2008 ◽  
Vol 73 (1) ◽  
pp. 41-53
Author(s):  
Aleksandra Rakic ◽  
Petar Mitrasinovic

The present study characterizes using molecular dynamics simulations the behavior of the GAA (1186-1188) hairpin triloops with their closing c-g base pairs in large ribonucleoligand complexes (PDB IDs: 1njn, 1nwy, 1jzx). The relative energies of the motifs in the complexes with respect to that in the reference structure (unbound form of rRNA; PDB ID: 1njp) display the trends that agree with those of the conformational parameters reported in a previous study1 utilizing the de novo pseudotorsional (?,?) approach. The RNA regions around the actual RNA-ligand contacts, which experience the most substantial conformational changes upon formation of the complexes were identified. The thermodynamic parameters, based on a two-state conformational model of RNA sequences containing 15, 21 and 27 nucleotides in the immediate vicinity of the particular binding sites, were evaluated. From a more structural standpoint, the strain of a triloop, being far from the specific contacts and interacting primarily with other parts of the ribosome, was established as a structural feature which conforms to the trend of the average values of the thermodynamic variables corresponding to the three motifs defined by the 15-, 21- and 27-nucleotide sequences. From a more functional standpoint, RNA-ligand recognition is suggested to be presumably dictated by the types of ligands in the complexes.


Author(s):  
Giulia Mancardi ◽  
Matteo Alberghini ◽  
Neus Aguilera-Porta ◽  
Monica Calatayud ◽  
Pietro Asinari ◽  
...  

Titanium dioxide nanoparticles have risen concerns about their possible toxicity and the European Food Safety Authority recently banned the use of TiO2 nano-additive in food products. Following the intent of relating nanomaterials atomic structure with their toxicity without having to conduct large scale experiments on living organisms, we investigate the aggregation of titanium dioxide nanoparticles using a multi-scale technique: starting from ab initio Density Functional Theory to get an accurate determination of the energetics and electronic structure, we switch to classical Molecular Dynamics simulations to calculate the Potential of Mean Force for the connection of two identical nanoparticles in water; the fitting of the latter by a set of mathematical equations is the key for the upscale. Lastly, we perform Brownian Dynamics simulations where each nanoparticle is a spherical bead. This coarsening strategy allows studying the aggregation of a few thousand nanoparticles. Applying this novel procedure, we find three new molecular descriptors, namely, the aggregation free energy and two numerical parameters used to correct the observed deviation from the aggregation kinetic described by the Smoluchowski theory. Molecular descriptors can be fed into QSAR models to predict the toxicity of a material knowing its physicochemical properties, without having to conduct large scale experiments on living organisms.


Rangifer ◽  
2008 ◽  
Vol 28 (1) ◽  
pp. 33
Author(s):  
Robert Serrouya ◽  
Bruce N. McLellan ◽  
Clayton D. Apps ◽  
Heiko U. Wittmer

Mountain caribou are an endangered ecotype of woodland caribou (Rangifer tarandus caribou) that live in highprecipitation, mountainous ecosystems of southeastern British Columbia and northern Idaho. The distribution and abundance of these caribou have declined dramatically from historical figures. Results from many studies have indicated that mountain caribou rely on old conifer forests for several life-history requirements including an abundance of their primary winter food, arboreal lichen, and a scarcity of other ungulates and their predators. These old forests often have high timber value, and understanding mountain caribou ecology at a variety of spatial scales is thus required to develop effective conservation strategies. Here we summarize results of studies conducted at three different spatial scales ranging from broad limiting factors at the population level to studies describing the selection of feeding sites within seasonal home ranges of individuals. The goal of this multi-scale review is to provide a more complete picture of caribou ecology and to determine possible shifts in limiting factors across scales. Our review produced two important results. First, mountain caribou select old forests and old trees at all spatial scales, signifying their importance for foraging opportunities as well as conditions required to avoid alternate ungulates and their predators. Second, relationships differ across scales. For example, landscapes dominated by roads and edges negatively affect caribou survival, but appear to attract caribou during certain times of the year. This juxtaposition of fine-scale behaviour with broad-scale vulnerability to predation could only be identified through integrated multi-scale analyses of resource selection. Consequently we suggest that effective management strategies for endangered species require an integrative approach across multiple spatial scales to avoid a focus that may be too narrow to maintain viable populations. Abstract in Norwegian / Sammendrag:Skala-avhengig økologi og truet fjellvillrein i Britisk ColumbiaFjellvillreinen i de nedbørsrike fjellområdene i sørøstre Britisk Columbia og nordlige Idaho som er en truet økotype av skogsreinen (Rangifer tarandus caribou), har blitt kraftig redusert både i utbredelse og antall. Mange studier har vist at denne økotypen er avhengig av vinterføden hengelav i gammel barskog hvor det også er få andre klovdyr og dermed få predatorer. Slik skog er også viktige hogstområder, og å forstå økologien til fjellvillreinen i forskjellige skaleringer er derfor nødvendig for å utvikle forvaltningsstrategier som kan berge og ta vare på denne reinen. Artikkelen gir en oversikt over slike arbeider: fra studier av begrensende faktorer på populasjonsnivå til studier av sesongmessige beiteplasser på individnivå. Hensikten er å få frem et mer helhetlig perspektiv på fjellvillreinen og finne hvordan de begrensende faktorene varierer etter skaleringen som er benyttet i studiet. Oversikten vår frembragte to viktige resultater; 1) Uansett skalering så velger dyrene gammel skog og gamle trær. 2) Dyrenes bruk av et område kan variere med benyttet skalering, for eksempel vil landskap utbygd med veier og hogstflater være ufordelaktig for overlevelsen, men synes likevel å kunne tiltrekke fjellvillreinen til visse tider av året. Forholdet mellom atferd ut fra fin-skalering og stor-skalering sårbarhet hva gjelder predasjon, ville kun blitt avdekket ved flere-skaleringsanalyse av hvordan ressursene benyttes. Ut fra dette foreslår vi at forvaltningsstrategier for truete bestander som eksempelvis fjellvillreinen, må baseres på tilnærminger ut fra ulike skaleringer for å hindre at et for snevert perspektiv kan begrense muligheten for vedvarende levedyktighet.


2021 ◽  
Author(s):  
Tom Pace ◽  
Hadi Rahmaninejad ◽  
Bin Sun ◽  
Peter Kekenes-Huskey

Silica-based materials including zeolites are commonly used for wide ranging applications including separations and catalysis.<br>Substrate transport rates in these materials often significantly influence the efficiency of such applications.<br>Two factors that contribute to transport rates include<br>1) the porosity of the silicate matrix and<br>2) non-bonding interactions between the diffusing species and the silicate surface.<br>Here, we utilize computer simulation to resolve the relative contribution of these factors to effective methane transport rates in a silicate channel.<br>Specifically, we develop a `homogenized' model of methane transport valid at micron and longer length scales that incorporates atomistic-scale kinetic information.<br>The atomistic-scale data are obtained from extensive molecular dynamics simulations that yield local diffusion coefficients and potentials of mean force.<br>With this model, we demonstrate how nuances in silicate hydration and silica/methane interactions impact 'macroscale' methane diffusion rates in bulk silicate materials.<br>This hybrid homogenization/molecular dynamics approach will be of general use for describing small molecule transport in materials with detailed molecular interactions.<br><br>


2019 ◽  
Author(s):  
Ian H. Kimball ◽  
Phuong T. Nguyen ◽  
Baldomero M. Olivera ◽  
Jon T. Sack ◽  
Vladimir Yarov-Yarovoy

AbstractThe voltage-gated sodium (Nav) channel subtype Nav1.7 plays a critical role in pain signaling, making it an important drug target. Here we studied the molecular interactions between μ-conotoxin KIIIA (KIIIA) and the human Nav1.7 channel (hNav1.7). We developed a structural model of hNav1.7 using Rosetta computational modeling and performed in silico docking of KIIIA using RosettaDock to predict residues forming specific pairwise contacts between KIIIA and hNav1.7. We experimentally validated these contacts using mutant cycle analysis. Comparison between our KIIIA-hNav1.7 model and the recently published cryo-EM structure of KIIIA-hNav1.2 revealed key similarities and differences between channel subtypes with potential implications for the molecular mechanism of toxin block. Our integrative approach, combining structural data with computational modeling, experimental validation, and molecular dynamics simulations will be useful for engineering molecular probes to study Nav channel function, and for rational design of novel biologics targeting specific Nav channels.


2019 ◽  
Vol 401 (1) ◽  
pp. 183-199 ◽  
Author(s):  
Parijat Majumder ◽  
Wolfgang Baumeister

Abstract Proteasomes are the principal molecular machines for the regulated degradation of intracellular proteins. These self-compartmentalized macromolecular assemblies selectively degrade misfolded, mistranslated, damaged or otherwise unwanted proteins, and play a pivotal role in the maintenance of cellular proteostasis, in stress response, and numerous other processes of vital importance. Whereas the molecular architecture of the proteasome core particle (CP) is universally conserved, the unfoldase modules vary in overall structure, subunit complexity, and regulatory principles. Proteasomal unfoldases are AAA+ ATPases (ATPases associated with a variety of cellular activities) that unfold protein substrates, and translocate them into the CP for degradation. In this review, we summarize the current state of knowledge about proteasome – unfoldase systems in bacteria, archaea, and eukaryotes, the three domains of life.


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