I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure

Capriotti, Emidio; Fariselli, Piero; Casadio, Rita

doi:10.1093/nar/gki375

Cited by 1,682 publications

(1,361 citation statements)

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“…The calculation of stability score is done in terms of change in free energy (DDG). Moreover, the MuStab [37] and I-Mutant 2.0 [6] servers were used for estimating the significance of mutations on the stability of the E2 protein. Both MuStab and I-Mutant 2.0 perform similar analysis with accuracy of 84.59 and 77% respectively.…”

Section: Mutation Analysismentioning

confidence: 99%

Potential entry inhibitors of the envelope protein (E2) of Chikungunya virus: in silico structural modeling, docking and molecular dynamic studies

et al. 2017

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Chikungunya fever is an arboviral infection caused by the Chikungunya virus (CHIKV) and is transmitted by Aedes mosquito. The envelope protein (E2) of Chikungunya virus is involved in attachment of virion with the host cell. The present study was conceptualized to determine the structure of E2 protein of CHIKV and to identify the potential viral entry inhibitors. The secondary and tertiary structure of E2 protein was determined using bioinformatics tools. The mutational analysis of the E2 protein suggested that mutations may stabilize or de-stabilize the structure which may affect the structure-function relationship. In silico screening of various compounds from different databases identified two lead molecules i.e. phenothiazine and bafilomycin. Molecular docking and MD simulation studies of the E2 protein and compound complexes was carried out. This analysis revealed that bafilomycin has high docking score and thus high binding affinity with E2 protein suggesting stable protein-ligand interaction. Further, MD simulations suggested that both the compounds were stabilizing E2 protein. Thus, bafilomycin and phenothiazine may be considered as the lead compounds in terms of potential entry inhibitor for CHIKV. Further, these results should be confirmed by comprehensive cell culture, cytotoxic assays and animal experiments. Certain derivatives of phenothiazines can also be explored in future studies for entry inhibitors against CHIKV. The present investigation thus provides insight into protein structural dynamics of the envelope protein of CHIKV. In addition the study also provides information on the dynamics of interaction of E2 protein with entry inhibitors that will contribute towards structure based drug design.

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Section: Mutation Analysismentioning

confidence: 99%

Potential entry inhibitors of the envelope protein (E2) of Chikungunya virus: in silico structural modeling, docking and molecular dynamic studies

et al. 2017

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“…The web-server iPTM-mLys, (http://www.jci-bioinfo.cn/iPTM-mLys) the first multi label PTM predictor was used to predict the identifying lysine PTM sites [33,34,35]. increase in protein stability [36]. For all the nsSNPs submissions the pH and temperature were set as 7 and 25 0 C respectively.…”

Section: Prediction Of Post -Translational Modification Sitesmentioning

confidence: 99%

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2017

RJLBPCS

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Aim: Proliferating cell nuclear antigen (PCNA) is an ancillary protein that assists in DNA replication and DNA repair process. Detection of mutations in PCNA gene or protein could be helpful to analyze many disorders relating to DNA replication and repair. In the present study, non-synonymous single nucleotide polymorphisms (nsSNPs) generated by missense mutation were studied using different computational methods to evaluate the nsSNPs that may be deleterious to PCNA function.Method: The missense nsSNPs were retrieved from the database of NCBI and subjected to functional prediction by the computational algorithms. The evolutionary conservation data of the PCNA protein was obtained from the ConSurf web server. The protein structural analysis for the variants was performed using I-Mutant, SPDB viewer and YASARA to check their structural variations and energy minimizations. Results: Out of the 42 nsSNPs, 5 nsSNPs namely rs780735449 (Q38R), rs1050525 (S39R), rs781573975 (E104G), rs772308650 (L182W) and rs753494859 (K248N) were identified as deleterious by using different computational algorithms. The evolutionary conservation data revealed that all the high risk nsSNPs positions were highly conserved and were either functional or structural residues in the protein. The I-Mutant tool had showed a decrease in the protein stability for the five high risk nsSNPs. A deviance in the energy minimization was observed for the variants with respect to the native protein. The RMSD (root mean square deviation) and TM (template modeling) values predicted that the mutants were structurally similar to the wild type protein. The PTM (post translational modifications) analysis using various in silico tools showed that S39R and K248N were putative PTM sites and through FTSite it was observed that these two variants were also involved in the ligand binding sites.Conclusion: Through the robust use of various in silico tools, five nsSNPs of PCNA protein were found to deleterious. Out of them two mutations at 39th and 248th positions (S39R & K248N) are to be further validated for their effect on the PCNA protein function.

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“…I-Mutant2.0 is a support vector machine (SMV) based tool for the automatic prediction of protein stability changes caused by single point mutations. I-Mutant2.0 predictions were performed starting either from the protein structure or, more importantly, from the protein sequence [24]. This program was trained and tested on a dataset derived from ProTherm [25], which is the most comprehensive available database of thermodynamic experimental data of free energy changes of protein stability caused by mutations under different conditions.…”

Section: Predicting Stability Changes Caused By Saps Using Support Vementioning

confidence: 99%

“…Of the 30 variants, 28 variants were found to be less stable using the I-Mutant 2.0 server (Table 1) [24]. Among these 28 variants, four variants showed a ∆∆G value <2.0.…”

Section: Identification Of Functional Variants By I-mutant 20mentioning

confidence: 99%

“…We rationally considered the 22 most potential detrimental point mutations (I16T, H21P, E24G, G27R, A57T, D68A, D114Y, G123E, I143T, C152R, C152W, C152Y, R168H, P181T, H244R, D249V, G274R, P280L, P280S, E285A, F295S and A305E) for further course of investigations because they were commonly found to be less stable, deleterious, and damaging by the I-Mutant2.0, SIFT and PolyPhen servers respectively [24,26,29]. We considered the statistical accuracy of these three programs, I-Mutant improves the quality of the prediction of the free energy change caused by single point protein mutations by adopting a hypothesis of thermodynamic reversibility of the existing experimental data.…”

Section: Rational Consideration Of Detrimental Point Mutationsmentioning

confidence: 99%

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Computational analysis of deleterious missense mutations in aspartoacylase that cause Canavan’s disease

Sreevishnupriya

Chandrasekaran

Senthilkumar

et al. 2012

Sci. China Life Sci.

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In this work, the most detrimental missense mutations of aspartoacylase that cause Canavan's disease were identified computationally and the substrate binding efficiencies of those missense mutations were analyzed. Out of 30 missense mutations, I-Mutant 2.0, SIFT and PolyPhen programs identified 22 variants that were less stable, deleterious and damaging respectively. Subsequently, modeling of these 22 variants was performed to understand the change in their conformations with respect to the native aspartoacylase by computing their root mean squared deviation (RMSD). Furthermore, the native protein and the 22 mutants were docked with the substrate NAA (N-Acetyl-Aspartic acid) to explain the substrate binding efficiencies of those detrimental missense mutations. Among the 22 mutants, the docking studies identified that 15 mutants caused lower binding affinity for NAA than the native protein. Finally, normal mode analysis determined that the loss of binding affinity of these 15 mutants was caused by altered flexibility in the amino acids that bind to NAA compared with the native protein. Thus, the present study showed that the majority of the substrate-binding amino acids in those 15 mutants displayed loss of flexibility, which could be the theoretical explanation of decreased binding affinity between the mutant aspartoacylases and NAA. missense mutation, Canavan's disease, aspartoacylase, NAA, flexibility Citation:Sreevishnupriya K, Chandrasekaran P, Senthilkumar A, et al. Computational analysis of deleterious missense mutations in aspartoacylase that cause Canavan's disease.

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I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure

Cited by 1,682 publications

References 7 publications

Potential entry inhibitors of the envelope protein (E2) of Chikungunya virus: in silico structural modeling, docking and molecular dynamic studies

Potential entry inhibitors of the envelope protein (E2) of Chikungunya virus: in silico structural modeling, docking and molecular dynamic studies

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Computational analysis of deleterious missense mutations in aspartoacylase that cause Canavan’s disease

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