scholarly journals A Computational Approach to Evaluate the Combined Effect of SARS-CoV-2 RBD Mutations and ACE2 Receptor Genetic Variants on Infectivity: The COVID-19 Host-Pathogen Nexus

2021 ◽  
Vol 11 ◽  
Author(s):  
Dana Ashoor ◽  
Noureddine Ben Khalaf ◽  
Maryam Marzouq ◽  
Hamdi Jarjanazi ◽  
Sadok Chlif ◽  
...  
Keyword(s):  
3D Model ◽  
Hydrophobic Interactions ◽  
Point Mutations ◽  
Computational Approach ◽  
Receptor Complex ◽  
Complex Stability ◽  
Virus Receptor ◽  
Contact Residues ◽  
The Stability ◽  
Virus Spreading

SARS-CoV-2 infectivity is largely determined by the virus Spike protein binding to the ACE2 receptor. Meanwhile, marked infection rate differences were reported between populations and individuals. To understand the disease dynamic, we developed a computational approach to study the implications of both SARS-CoV-2 RBD mutations and ACE2 polymorphism on the stability of the virus-receptor complex. We used the 6LZG PDB RBD/ACE2 3D model, the mCSM platform, the LigPlot+ and PyMol software to analyze the data on SARS-CoV-2 mutations and ACE variants retrieved from GISAID and Ensembl/GnomAD repository. We observed that out of 351 RBD point mutations, 83% destabilizes the complex according to free energy (ΔΔG) differences. We also spotted variations in the patterns of polar and hydrophobic interactions between the mutations occurring in 15 out of 18 contact residues. Similarly, comparison of the effect on the complex stability of different ACE2 variants showed that the pattern of molecular interactions and the complex stability varies also according to ACE2 polymorphism. We infer that it is important to consider both ACE2 variants and circulating SARS-CoV-2 RBD mutations to assess the stability of the virus-receptor association and evaluate infectivity. This approach might offers a good molecular ground to mitigate the virus spreading.

scholarly journals A computational approach to evaluate the combined effect of SARS-CoV-2 RBD mutations and ACE2 receptor genetic variants on infectivity: The COVID-19 host-pathogen nexus

2020 ◽  
Author(s):  
Dana Ashoor ◽  
Noureddine Ben Khalaf ◽  
Maryam Marzouq ◽  
Hamdi Jarjanazi ◽  
Sadok Chelif ◽  
...  
Keyword(s):  
3D Model ◽  
Hydrophobic Interactions ◽  
Point Mutations ◽  
Computational Approach ◽  
Receptor Complex ◽  
Complex Stability ◽  
Virus Receptor ◽  
Contact Residues ◽  
The Stability ◽  
Virus Spreading

Abstract: SARS-CoV-2 infectivity is largely determined by the virus Spike protein binding to the ACE2 receptor. Meanwhile, marked infection rate differences were reported between populations and individuals. To understand the disease dynamic, we developed a computational approach to study the implications of both SARS-CoV-2 RBD mutations and ACE2 polymorphism on the stability of the virus-receptor complex. We used the 6LZG PDB RBD/ACE2 3D model, the mCSM platform, the LigPlot+ and PyMol software to analyze the data on SARS-CoV-2 mutations and ACE variants retrieved from GISAID and Ensembl/GnomAD repository. We observed that out of 351 RBD point mutations, 83% destabilizes the complex according to free energy (∆∆G) differences. We also spotted variations in the patterns of polar and hydrophobic interactions between the mutations occurring in 15 out of 18 contact residues. Similarly, comparison of the effect on the complex stability of different ACE2 variants showed that the pattern of molecular interactions and the complex stability varies also according to ACE2 polymorphism. We infer that it is important to consider both ACE2 variants and circulating SARS-CoV-2 RBD mutations to assess the stability of the virus-receptor association and evaluate infectivity. This approach might offers a good molecular ground to mitigate the virus spreading.

Coaction of Electrostatic and Hydrophobic Interactions: Dynamic Constraints on Disordered TrkA Juxtamembrane Domain

2019 ◽  
Author(s):  
Zichen Wang ◽  
Huaxun Fan ◽  
Xiao Hu ◽  
John Khamo ◽  
Jiajie Diao ◽  
...  
Keyword(s):  
Single Molecule ◽  
Protein Function ◽  
Hydrophobic Interactions ◽  
Transmembrane Helix ◽  
Point Mutations ◽  
Salt Bridge ◽  
Receptor Activation ◽  
Membrane Dynamics ◽  
Juxtamembrane Domain ◽  
Joint Work

<p>The receptor tyrosine kinase family transmits signals into cell via a single transmembrane helix and a flexible juxtamembrane domain (JMD). Membrane dynamics makes it challenging to study the structural mechanism of receptor activation experimentally. In this study, we employ all-atom molecular dynamics with Highly Mobile Membrane-Mimetic to capture membrane interactions with the JMD of tropomyosin receptor kinase A (TrkA). We find that PIP<sub>2 </sub>lipids engage in lasting binding to multiple basic residues and compete with salt bridge within the peptide. We discover three residues insertion into the membrane, and perturb it through computationally designed point mutations. Single-molecule experiments indicate the contribution from hydrophobic insertion is comparable to electrostatic binding, and in-cell experiments show that enhanced TrkA-JMD insertion promotes receptor ubiquitination. Our joint work points to a scenario where basic and hydrophobic residues on disordered domains interact with lipid headgroups and tails, respectively, to restrain flexibility and potentially modulate protein function.</p>

scholarly journals Mechanisms of Transforming Growth Factor-β Receptor Endocytosis and Intracellular Sorting Differ between Fibroblasts and Epithelial Cells

2001 ◽  
Vol 12 (3) ◽  
pp. 675-684 ◽  
Author(s):  
Jules J.E. Doré ◽  
Diying Yao ◽  
Maryanne Edens ◽  
Nandor Garamszegi ◽  
Elizabeth L. Sholl ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Ligand Binding ◽  
Transforming Growth Factor ◽  
Point Mutations ◽  
Type I ◽  
Receptor Complex ◽  
Type Ii ◽  
Down Regulation ◽  
Β Receptor

Transforming growth factor-βs (TGF-β) are multifunctional proteins capable of either stimulating or inhibiting mitosis, depending on the cell type. These diverse cellular responses are caused by stimulating a single receptor complex composed of type I and type II receptors. Using a chimeric receptor model where the granulocyte/monocyte colony-stimulating factor receptor ligand binding domains are fused to the transmembrane and cytoplasmic signaling domains of the TGF-β type I and II receptors, we wished to describe the role(s) of specific amino acid residues in regulating ligand-mediated endocytosis and signaling in fibroblasts and epithelial cells. Specific point mutations were introduced at Y182, T200, and Y249 of the type I receptor and K277 and P525 of the type II receptor. Mutation of either Y182 or Y249, residues within two putative consensus tyrosine-based internalization motifs, had no effect on endocytosis or signaling. This is in contrast to mutation of T200 to valine, which resulted in ablation of signaling in both cell types, while only abolishing receptor down-regulation in fibroblasts. Moreover, in the absence of ligand, both fibroblasts and epithelial cells constitutively internalize and recycle the TGF-β receptor complex back to the plasma membrane. The data indicate fundamental differences between mesenchymal and epithelial cells in endocytic sorting and suggest that ligand binding diverts heteromeric receptors from the default recycling pool to a pathway mediating receptor down-regulation and signaling.

scholarly journals Computational Approach to Identify Mutations in Genes of Notch Signaling Pathway and Its Association with OSCC

2020 ◽  
pp. 84-92
Author(s):  
Madhumithaa Sivarajan ◽  
A. S. Smiline Girija ◽  
A. Paramasivam ◽  
J. Vijayashree Priyadharsini
Keyword(s):  
Notch Signaling ◽  
Signaling Pathway ◽  
Tumor Development ◽  
Suppressor Gene ◽  
Notch Signaling Pathway ◽  
Computational Approach ◽  
Notch Signalling ◽  
Cell Renewal ◽  
Data Set ◽  
The Stability

Derailments in signal transduction pathways are associated with the development of tumors. One such vital pathway is the Notch signaling pathway which is associated with various processes of carcinogenesis such as proliferation of cells, cell renewal, angiogenesis and oncogenic microenvironment preservation. Interestingly, Notch also plays a pivotal role in tumor development by acting as an oncogene as well as tumor suppressor gene. In view of this fact, the present study was designed to analyze mutations in Notch signalling pathway which might have a crucial role in the etiology of oral squamous cell carcinoma (OSCC) using computational approach. The Cancer Gene Atlas data set hosted in the cBioportal was used in the present study. These samples were queried for the presence of mutations in Notch signalling genes which included a predefined list of 55 genes. Further, the Oncoprint data obtained was compared to that of gnomAD database which identified novel and reported mutations in the genes analyzed. Additionally, I-Mutant and MutPred analysis was carried out to determine the stability and pathogenicity of the variations recorded. Among 55 genes analysed, SPEN gene was shown to possess the highest frequency of mutation (5%) followed by FBXW7, Notch1, EP300, NUMB, and RBPJL genes. Most of the mutations identified were novel as assessed using the control dataset from the gnomAD database. The stability of the protein was found to decrease upon nucleotide substitution. Finally, the MutPred score revealed that most of the mutant proteins were pathogenic.  Several novel mutations have been identified in the pathway analyzed. Functional analysis of these variants using experimental approaches would aid in dissecting their association with OSCC.

scholarly journals Unraveling the stability landscape of mutations in the SARS-CoV-2 receptor-binding domain

2020 ◽  
Author(s):  
Mohamed Raef Smaoui ◽  
Hamdi Yahyaoui
Keyword(s):  
Receptor Binding ◽  
Single Point ◽  
Protein Structures ◽  
Point Mutations ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Point Mutant ◽  
The Stability ◽  
Spike Proteins

Abstract The interaction between the receptor-binding domain of the SARS-CoV-2 spike glycoprotein and the ACE2 enzyme is believed to be the entry point of the virus into various cells in the body, including the lungs, heart, liver, and kidneys. The current focus of several therapeutic design efforts explore attempts at affecting the binding interaction between the two proteins to limit the activity of the virus and disease progression. In this work, we analyze the stability of the spike protein under all possible single-point mutations in the receptor-binding domain and computationally explore mutations that can affect the binding with the ACE2 enzyme. We unravel the mutation landscape of the receptor region and assess the toxicity potential of single and multi-point mutations, generating insights for future vaccine efforts on potential mutations that might further stabilize the spike protein and increase its infectivity. We developed a tool, called SpikeMutator, to construct full atomic protein structures of the mutant spike proteins and shared a database of 3,800 single-point mutant structures. We analyzed the recent 65,000 reported spike sequences across the globe and observed the emergence of stable multi-point mutant structures. Using the landscape, we searched through 7.5 million possible 2-point mutation combinations and report that the (R355D K424E) mutation produces one of the strongest spike proteins that therapeutic efforts should investigate for the sake of developing an effective vaccine.

Protein intrachain contact prediction with most interacting residues (MIR)

2014 ◽  
Vol 10 (4) ◽  
Author(s):  
Ruben Acuña ◽  
Zoé Lacroix ◽  
Nikolaos Papandreou ◽  
Jacques Chomilier
Keyword(s):  
Structural Changes ◽  
Hydrophobic Interactions ◽  
Three Dimensional ◽  
Accessible Surface Area ◽  
Dimensional Structure ◽  
Closed Loops ◽  
Folding Process ◽  
Folding Nucleus ◽  
Accessible Surface ◽  
The Stability

AbstractThe transition state ensemble during the folding process of globular proteins occurs when a sufficient number of intrachain contacts are formed, mainly, but not exclusively, due to hydrophobic interactions. These contacts are related to the folding nucleus, and they contribute to the stability of the native structure, although they may disappear after the energetic barrier of transition states has been passed. A number of structure and sequence analyses, as well as protein engineering studies, have shown that the signature of the folding nucleus is surprisingly present in the native three-dimensional structure, in the form of closed loops, and also in the early folding events. These findings support the idea that the residues of the folding nucleus become buried in the very first folding events, therefore helping the formation of closed loops that act as anchor structures, speed up the process, and overcome the Levinthal paradox. We present here a review of an algorithm intended to simulate in a discrete space the early steps of the folding process. It is based on a Monte Carlo simulation where perturbations, or moves, are randomly applied to residues within a sequence. In contrast with many technically similar approaches, this model does not intend to fold the protein but to calculate the number of non-covalent neighbors of each residue, during the early steps of the folding process. Amino acids along the sequence are categorized as most interacting residues (MIRs) or least interacting residues. The MIR method can be applied under a variety of circumstances. In the cases tested thus far, MIR has successfully identified the exact residue whose mutation causes a switch in conformation. This follows with the idea that MIR identifies residues that are important in the folding process. Most MIR positions correspond to hydrophobic residues; correspondingly, MIRs have zero or very low accessible surface area. Alongside the review of the MIR method, we present a new postprocessing method called smoothed MIR (SMIR), which refines the original MIR method by exploiting the knowledge of residue hydrophobicity. We review known results and present new ones, focusing on the ability of MIR to predict structural changes, secondary structure, and the improved precision with the SMIR method.

scholarly journals Interaction of caldesmon with phospholipids

1993 ◽  
Vol 291 (2) ◽  
pp. 403-408 ◽  
Author(s):  
E A Czuryło ◽  
J Zborowski ◽  
R Dabrowska
Keyword(s):  
Fluorescence Spectroscopy ◽  
Hydrophobic Interactions ◽  
Tryptophan Fluorescence ◽  
Terminal Part ◽  
Strong Binding ◽  
Terminal Fragment ◽  
Electrostatic And Hydrophobic Interactions ◽  
The Stability

The interaction of caldesmon with liposomes composed of various phospholipids has been examined by tryptophan fluorescence spectroscopy. The results indicate that caldesmon makes its strongest complex with phosphatidylserine (PS) vesicles (Kass. = 1.45 x 10(5) M-1). Both electrostatic and hydrophobic interactions contribute to the stability of this complex. The site for strong binding of PS seems to be located in the N-terminal part of the 34 kDa C-terminal fragment of caldesmon. Binding of PS at this site results in displacement of calmodulin from its complex with caldesmon.

scholarly journals Adding levels of complexity enhances robustness and evolvability in a multilevel genotype–phenotype map

2018 ◽  
Vol 15 (138) ◽  
pp. 20170516 ◽  
Author(s):  
Pablo Catalán ◽  
Andreas Wagner ◽  
Susanna Manrubia ◽  
José A. Cuesta
Keyword(s):  
Protein Folding ◽  
Regulatory Networks ◽  
Phenotypic Expression ◽  
Point Mutations ◽  
Skewed Distribution ◽  
Cellular Biology ◽  
Folding Model ◽  
Number Of Genes ◽  
Genotype Space ◽  
The Stability

Robustness and evolvability are the main properties that account for the stability and accessibility of phenotypes. They have been studied in a number of computational genotype–phenotype maps. In this paper, we study a metabolic genotype–phenotype map defined in toyLIFE , a multilevel computational model that represents a simplified cellular biology. toyLIFE includes several levels of phenotypic expression, from proteins to regulatory networks to metabolism. Our results show that toyLIFE shares many similarities with other seemingly unrelated computational genotype–phenotype maps. Thus, toyLIFE shows a high degeneracy in the mapping from genotypes to phenotypes, as well as a highly skewed distribution of phenotypic abundances. The neutral networks associated with abundant phenotypes are highly navigable, and common phenotypes are close to each other in genotype space. All of these properties are remarkable, as toyLIFE is built on a version of the HP protein-folding model that is neither robust nor evolvable: phenotypes cannot be mutually accessed through point mutations. In addition, both robustness and evolvability increase with the number of genes in a genotype. Therefore, our results suggest that adding levels of complexity to the mapping of genotypes to phenotypes and increasing genome size enhances both these properties.

scholarly journals Theoretical Description of R–X⋯NH3 Halogen Bond Complexes: Effect of the R Group on the Complex Stability and Sigma-Hole Electron Depletion

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 530
Author(s):  
Juan Zurita ◽  
Vladimir Rodriguez ◽  
Cesar Zambrano ◽  
Jose Ramón Mora ◽  
Luis Rincón ◽  
...  
Keyword(s):  
Halogen Bond ◽  
Theoretical Description ◽  
Binding Energies ◽  
Complex Stability ◽  
Ethyl Vinyl ◽  
Cooperative Effects ◽  
Pair Density ◽  
Leibler Divergence ◽  
Sigma Hole ◽  
The Stability

In the present work, a number of R–X⋯NH3 (X = Cl, Br, and I) halogen bonded systems were theoretical studied by means of DFT calculations performed at the ωB97XD/6-31+G(d,p) level of theory in order to get insights on the effect of the electron-donating or electron-withdrawing character of the different R substituent groups (R = halogen, methyl, partially fluorinated methyl, perfluoro-methyl, ethyl, vinyl, and acetyl) on the stability of the halogen bond. The results indicate that the relative stability of the halogen bond follows the Cl < Br < I trend considering the same R substituent whereas the more electron-withdrawing character of the R substituent the more stable the halogen bond. Refinement of the latter results, performed at the MP2/6-31+G(d,p) level showed that the DFT and the MP2 binding energies correlate remarkably well, suggesting that the Grimme’s type dispersion-corrected functional produces reasonable structural and energetic features of halogen bond systems. DFT results were also observed to agree with more refined calculations performed at the CCSD(T) level. In a further stage, a more thorough analysis of the R–Br⋯NH3 complexes was performed by means of a novel electron localization/delocalization tool, defined in terms of an Information Theory, IT, based quantity obtained from the conditional pair density. For the latter, our in-house developed C++/CUDA program, called KLD (acronym of Kullback–Leibler divergence), was employed. KLD results mapped onto the one-electron density plotted at a 0.04 a.u. isovalue, showed that (i) as expected, the localized electron depletion of the Br sigma-hole is largely affected by the electron-withdrawing character of the R substituent group and (ii) the R–X bond is significantly polarized due to the presence of the NH3 molecule in the complexes. The afore-mentioned constitutes a clear indication of the dominant character of electrostatics on the stabilization of halogen bonds in agreement with a number of studies reported in the main literature. Finally, the cooperative effects on the [Br—CN]n system (n = 1–8) was evaluated at the MP2/6-31+G(d,p) level, where it was observed that an increase of about ~14.2% on the complex stability is obtained when going from n = 2 to n = 8. The latter results were corroborated by the analysis of the changes on the Fermi-hole localization pattern on the halogen bond zones, which suggests an also important contribution of the electron correlation in the stabilization of these systems.

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