Comparative Study of Elastic Network Model and Protein Contact Network for Protein Complexes: The Hemoglobin Case

Hu, Guang; Paola, Luisa Di; Liang, Zhongjie; Giuliani, Alessandro

doi:10.1155/2017/2483264

Cited by 20 publications

(10 citation statements)

References 80 publications

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“…Since RMSD and Rg analysis showed subtle changes associated with SNV presence, network analysis was performed to obtain a more thorough and robust understanding of variant effects on the CA-II protein. Through previous research, network analyses has proved useful in the identification of key regions and residues essential for communication, function and stability in proteins [70,71,72]. In 2017, Brown et al [41] utilized DRN to successfully investigate SNV effects on protein dynamics.…”

Section: Resultsmentioning

confidence: 99%

Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with α-Carbonic Anhydrase II Deficiency

2019

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Human carbonic anhydrase II (CA-II) is a Zinc (Zn2+) metalloenzyme responsible for maintenance of acid-base balance within the body through the reversible hydration of CO2 to produce protons (H+) and bicarbonate (BCT). Due to its importance, alterations to the amino acid sequence of the protein as a result of single nucleotide variations (nsSNVs) have detrimental effects on homeostasis. Six pathogenic CA-II nsSNVs, K18E, K18Q, H107Y, P236H, P236R and N252D were identified, and variant protein models calculated using homology modeling. The effect of each nsSNV was analyzed using motif analysis, molecular dynamics (MD) simulations, principal component (PCA) and dynamic residue network (DRN) analysis. Motif analysis identified 11 functionally important motifs in CA-II. RMSD data indicated subtle SNV effects, while PCA analysis revealed that the presence of BCT results in greater conformational sampling and free energy in proteins. DRN analysis showed variant allosteric effects, and the average betweenness centrality (BC) calculations identified Glu117 as the most important residue for communication in CA-II. The presence of BCT was associated with a reduction to Glu117 usage in all variants, suggesting implications for Zn2+ dissociation from the CA-II active site. In addition, reductions to Glu117 usage are associated with increases in the usage of the primary and secondary Zn2+ ligands; His94, His96, His119 and Asn243 highlighting potential compensatory mechanisms to maintain Zn2+ within the active site. Compared to traditional MD simulation investigation, DRN analysis provided greater insights into SNV mechanism of action, indicating its importance for the study of missense mutation effects in proteins and, in broader terms, precision medicine related research.

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Section: Resultsmentioning

confidence: 99%

Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with α-Carbonic Anhydrase II Deficiency

2019

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“…In Figure 2, a collection of plots, all accessible from the Analysis Tools window, is given. Figure 2C and Figure 2C shows two scatter plots of particular interest: in the first one, the closeness centrality is seen to be correlated to fluctuation profiles from ANM, confirming its usefulness as a rigidity descriptor (87). In Figure 2D, high betweenness-centrality values are seen to coincide well with highly conserved residues, highlighting a relationship between sequence evolution and dynamic cross-talk within the ß-lactamase structure.…”

Section: Resultsmentioning

confidence: 72%

ProSNEx: a web-based application for exploration and analysis of protein structures using network formalism

Aydinkal

Serçinoğlu

Ozbek

2019

Nucleic Acids Research

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ProSNEx (Protein Structure Network Explorer) is a web service for construction and analysis of Protein Structure Networks (PSNs) alongside amino acid flexibility, sequence conservation and annotation features. ProSNEx constructs a PSN by adding nodes to represent residues and edges between these nodes using user-specified interaction distance cutoffs for either carbon-alpha, carbon-beta or atom-pair contact networks. Different types of weighted networks can also be constructed by using either (i) the residue-residue interaction energies in the format returned by gRINN, resulting in a Protein Energy Network (PEN); (ii) the dynamical cross correlations from a coarse-grained Normal Mode Analysis (NMA) of the protein structure; (iii) interaction strength. Upon construction of the network, common network metrics (such as node centralities) as well as shortest paths between nodes and k-cliques are calculated. Moreover, additional features of each residue in the form of conservation scores and mutation/natural variant information are included in the analysis. By this way, tool offers an enhanced and direct comparison of network-based residue metrics with other types of biological information. ProSNEx is free and open to all users without login requirement at http://prosnex-tool.com.

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“…Node inter-connectivity is finally used to highlight cluster-forming nodes, where a cluster is a set of connected amino acids in a graph. For details, see [13] , [17] , [24] .…”

Section: Theorymentioning

confidence: 99%

Structural deformability induced in proteins of potential interest associated with COVID-19 by binding of homologues present in ivermectin: Comparative study based in elastic networks models

González

Hurtado-León

Lossada

et al. 2021

Journal of Molecular Liquids

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The COVID-19 pandemic has accelerated the study of the potential of multi-target drugs (MTDs). The mixture of homologues called ivermectin (avermectin-B1a + avermectin-B1b) has been shown to be a MTD with potential antiviral activity against SARS-CoV-2 in vitro . However, there are few reports on the effect of each homologue on the flexibility and stiffness of proteins associated with COVID-19, described as ivermectin targets. We observed that each homologue was stably bound to identified proteinsthe proteins studied and were able to induce detectable changes with Elastic Network Models (ENMs). The perturbations induced by each homologue were characteristic of each compound and, in turn, were represented by a disruption of native intramolecular networks (interactions between residues). The homologues were able to slightly modify the conformation and stability of the connection points between the Cα atoms of the residues that make up the structural network of proteins (nodes), compared to free proteins. Each homologue was able to modified differently the distribution of quasi-rigid regions of the proteins, which could theoretically alter their biological activities. These results could provide a biophysical-computational view of the potential MTD mechanism that has been reported for ivermectin.

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Comparative Study of Elastic Network Model and Protein Contact Network for Protein Complexes: The Hemoglobin Case

Cited by 20 publications

References 80 publications

Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with α-Carbonic Anhydrase II Deficiency

Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with α-Carbonic Anhydrase II Deficiency

ProSNEx: a web-based application for exploration and analysis of protein structures using network formalism

Structural deformability induced in proteins of potential interest associated with COVID-19 by binding of homologues present in ivermectin: Comparative study based in elastic networks models

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