mCSM-AB: a web server for predicting antibody–antigen affinity changes upon mutation with graph-based signatures

Pires, Douglas E V; Ascher, David B.

doi:10.1093/nar/gkw458

Cited by 105 publications

(89 citation statements)

References 26 publications

(21 reference statements)

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“…The effect of the differences on the protein-protein binding affinity between the alpha and beta chains to form the HLA II complex were predicted using mCSM-PPI [35]. The effect of the changes on the binding affinity of the HLA II complex for a model peptide were also analysed using mCSM-PPI, as previously described [36], mCSM-lig [37], and mCSM-AB [38]. These computational approaches represent the wild-type residues structural and chemical environment of a residue as a graph-based signature in order to quantitatively determine the change upon mutation in Gibb’s Free Energy of stability or binding.…”

Section: Methodsmentioning

confidence: 99%

The Presence, Persistence and Functional Properties of Plasmodium vivax Duffy Binding Protein II Antibodies Are Influenced by HLA Class II Allelic Variants

et al. 2016

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BackgroundThe human malaria parasite Plasmodium vivax infects red blood cells through a key pathway that requires interaction between Duffy binding protein II (DBPII) and its receptor on reticulocytes, the Duffy antigen/receptor for chemokines (DARC). A high proportion of P. vivax-exposed individuals fail to develop antibodies that inhibit DBPII-DARC interaction, and genetic factors that modulate this humoral immune response are poorly characterized. Here, we investigate if DBPII responsiveness could be HLA class II-linked.Methodology/Principal FindingsA community-based open cohort study was carried out in an agricultural settlement of the Brazilian Amazon, in which 336 unrelated volunteers were genotyped for HLA class II (DRB1, DQA1 and DQB1 loci), and their DBPII immune responses were monitored over time (baseline, 6 and 12 months) by conventional serology (DBPII IgG ELISA-detected) and functional assays (inhibition of DBPII–erythrocyte binding). The results demonstrated an increased susceptibility of the DRB1*13:01 carriers to develop and sustain an anti-DBPII IgG response, while individuals with the haplotype DRB1*14:02-DQA1*05:03-DQB1*03:01 were persistent non-responders. HLA class II gene polymorphisms also influenced the functional properties of DBPII antibodies (BIAbs, binding inhibitory antibodies), with three alleles (DRB1*07:01, DQA1*02:01 and DQB1*02:02) comprising a single haplotype linked with the presence and persistence of the BIAbs response. Modelling the structural effects of the HLA-DRB1 variants revealed a number of differences in the peptide-binding groove, which is likely to lead to altered antigen binding and presentation profiles, and hence may explain the differences in subject responses.Conclusions/SignificanceThe current study confirms the heritability of the DBPII antibody response, with genetic variation in HLA class II genes influencing both the development and persistence of IgG antibody responses. Cellular studies to increase knowledge of the binding affinities of DBPII peptides for class II molecules linked with good or poor antibody responses might lead to the development of strategies for controlling the type of helper T cells activated in response to DBPII.

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Section: Methodsmentioning

confidence: 99%

The Presence, Persistence and Functional Properties of Plasmodium vivax Duffy Binding Protein II Antibodies Are Influenced by HLA Class II Allelic Variants

et al. 2016

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“…We have previously used the concept of graph-based signatures to model a broad range of molecular phenomena. This has included the effect of mutations on protein stability ( 17 , 18 ), and interactions with other proteins ( 18 , 19 ), small molecules ( 20 – 22 ) and metal ions ( 8 ). We also used these signatures to scalably look at, for the first time, the effects of mutations on protein–nucleic acid binding affinities ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

mCSM–NA: predicting the effects of mutations on protein–nucleic acids interactions

Pires

Ascher

2017

Nucleic Acids Research

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Over the past two decades, several computational methods have been proposed to predict how missense mutations can affect protein structure and function, either by altering protein stability or interactions with its partners, shedding light into potential molecular mechanisms giving rise to different phenotypes. Effectively and efficiently predicting consequences of mutations on protein–nucleic acid interactions, however, remained until recently a great and unmet challenge. Here we report an updated webserver for mCSM–NA, the only scalable method we are aware of capable of quantitatively predicting the effects of mutations in protein coding regions on nucleic acid binding affinities. We have significantly enhanced the original method by including a pharmacophore modelling and information of nucleic acid properties into our graph-based signatures, considering the reverse mutation and by using a refined, more reliable data set, based on a new release of the ProNIT database, which has significantly improved the reliability and applicability of the methodology. Our new predictive model was capable of achieving a correlation coefficient of up to 0.70 on cross-validation and 0.68 on blind-tests, outperforming its previous version. The server is freely available via a user-friendly web interface at: http://structure.bioc.cam.ac.uk/mcsm_na.

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“…mCSM-AB is an online bioinformatic server (http://bleoberis.bioc.cam.ac.uk/mcsm_ab/prediction) that relies on graph-based signatures to predict antibody–antigen affinity changes upon mutation 47 .…”

Section: Methodsmentioning

confidence: 99%

Delineation of B-cell Epitopes of Salmonella enterica serovar Typhi Hemolysin E: Potential antibody therapeutic target

Chin

Lai

Choong

et al. 2017

Sci Rep

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Hemolysin E (HlyE) is an immunogenic novel pore-forming toxin involved in the pathogenesis of typhoid fever. Thus, mapping of B-cell epitopes of Salmonella enterica serovar Typhi (S. Typhi) is critical to identify key immunogenic regions of HlyE. A random 20-mer peptide library was used for biopanning with enriched anti-HlyE polyclonal antibodies from typhoid patient sera. Bioinformatic tools were used to refine, analyze and map the enriched peptide sequences against the protein to identify the epitopes. The analysis identified both linear and conformational epitopes on the HlyE protein. The predicted linear GAAAGIVAG and conformational epitope PYSQESVLSADSQNQK were further validated against the pooled sera. The identified epitopes were then used to isolate epitope specific monoclonal antibodies by antibody phage display. Monoclonal scFv antibodies were enriched for both linear and conformational epitopes. Molecular docking was performed to elucidate the antigen-antibody interaction of the monoclonal antibodies against the epitopes on the HlyE monomer and oligomer structure. An in-depth view of the mechanistic and positional characteristics of the antibodies and epitope for HlyE was successfully accomplished by a combination of phage display and bioinformatic analysis. The predicted function and structure of the antibodies highlights the possibility of utilizing the antibodies as neutralizing agents for typhoid fever.

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mCSM-AB: a web server for predicting antibody–antigen affinity changes upon mutation with graph-based signatures

Cited by 105 publications

References 26 publications

The Presence, Persistence and Functional Properties of Plasmodium vivax Duffy Binding Protein II Antibodies Are Influenced by HLA Class II Allelic Variants

The Presence, Persistence and Functional Properties of Plasmodium vivax Duffy Binding Protein II Antibodies Are Influenced by HLA Class II Allelic Variants

mCSM–NA: predicting the effects of mutations on protein–nucleic acids interactions

Delineation of B-cell Epitopes of Salmonella enterica serovar Typhi Hemolysin E: Potential antibody therapeutic target

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