MCSM-PPI2: Predicting the Effects of Mutations on Protein-protein Interactions

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2019 May 23

PMID 31114883

Citations 154

Authors

Carlos H M Rodrigues

Yoochan Myung

Douglas E V Pires

David B Ascher

Affiliations

Soon will be listed here.

Abstract

Protein-protein Interactions are involved in most fundamental biological processes, with disease causing mutations enriched at their interfaces. Here we present mCSM-PPI2, a novel machine learning computational tool designed to more accurately predict the effects of missense mutations on protein-protein interaction binding affinity. mCSM-PPI2 uses graph-based structural signatures to model effects of variations on the inter-residue interaction network, evolutionary information, complex network metrics and energetic terms to generate an optimised predictor. We demonstrate that our method outperforms previous methods, ranking first among 26 others on CAPRI blind tests. mCSM-PPI2 is freely available as a user friendly webserver at http://biosig.unimelb.edu.au/mcsm_ppi2/.

Citing Articles

Proximity proteomics reveals a mechanism of fatty acid transfer at lipid droplet-mitochondria- endoplasmic reticulum contact sites.

Bezawork-Geleta A, Devereux C, Keenan S, Lou J, Cho E, Nie S Nat Commun. 2025; 16(1):2135.

PMID: 40032835 PMC: 11876333. DOI: 10.1038/s41467-025-57405-5.

Decoding the effects of mutation on protein interactions using machine learning.

Xu W, Li A, Zhao Y, Peng Y Biophys Rev (Melville). 2025; 6(1):011307.

PMID: 40013003 PMC: 11857871. DOI: 10.1063/5.0249920.

Predicting Antibody Affinity Changes upon Mutation Based on Unbound Protein Structures.

Chen Z, He S, Chi X, Bo X Int J Mol Sci. 2025; 26(3).

PMID: 39941111 PMC: 11818220. DOI: 10.3390/ijms26031343.

Integrative genomic analyses combined with molecular dynamics simulations reveal the impact of deleterious mutations of Bcl-2 gene on the apoptotic machinery and implications in carcinogenesis.

Elamin G, Zhang Z, Dwarka D, Kasumbwe K, Mellem J, Mkhwanazi N Front Genet. 2025; 15:1502152.

PMID: 39840282 PMC: 11747654. DOI: 10.3389/fgene.2024.1502152.

Decoding the functional impact of the cancer genome through protein-protein interactions.

Fu H, Mo X, Ivanov A Nat Rev Cancer. 2025; 25(3):189-208.

PMID: 39810024 DOI: 10.1038/s41568-024-00784-6.

References

Berman H, Westbrook J, Feng Z, Gilliland G, Bhat T, Weissig H . The Protein Data Bank. Nucleic Acids Res. 1999; 28(1):235-42. PMC: 102472. DOI: 10.1093/nar/28.1.235. View

Kawashima S, Kanehisa M . AAindex: amino acid index database. Nucleic Acids Res. 1999; 28(1):374. PMC: 102411. DOI: 10.1093/nar/28.1.374. View

Kollman P, Massova I, Reyes C, Kuhn B, Huo S, Chong L . Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Acc Chem Res. 2000; 33(12):889-97. DOI: 10.1021/ar000033j. View

Kortemme T, Baker D . A simple physical model for binding energy hot spots in protein-protein complexes. Proc Natl Acad Sci U S A. 2002; 99(22):14116-21. PMC: 137846. DOI: 10.1073/pnas.202485799. View

Janin J, Henrick K, Moult J, Ten Eyck L, Sternberg M, Vajda S . CAPRI: a Critical Assessment of PRedicted Interactions. Proteins. 2003; 52(1):2-9. DOI: 10.1002/prot.10381. View

Chuderland D, Seger R . Protein-protein interactions in the regulation of the extracellular signal-regulated kinase. Mol Biotechnol. 2005; 29(1):57-74. DOI: 10.1385/MB:29:1:57. View

Schymkowitz J, Borg J, Stricher F, Nys R, Rousseau F, Serrano L . The FoldX web server: an online force field. Nucleic Acids Res. 2005; 33(Web Server issue):W382-8. PMC: 1160148. DOI: 10.1093/nar/gki387. View

Grant B, Rodrigues A, ElSawy K, McCammon J, Caves L . Bio3d: an R package for the comparative analysis of protein structures. Bioinformatics. 2006; 22(21):2695-6. DOI: 10.1093/bioinformatics/btl461. View

Paumi C, Menendez J, Arnoldo A, Engels K, Iyer K, Thaminy S . Mapping protein-protein interactions for the yeast ABC transporter Ycf1p by integrated split-ubiquitin membrane yeast two-hybrid analysis. Mol Cell. 2007; 26(1):15-25. DOI: 10.1016/j.molcel.2007.03.011. View

10.

Gao J, Li W, Feng S, Yuan Y, Wan D, Han W . A protein-protein interaction network of transcription factors acting during liver cell proliferation. Genomics. 2008; 91(4):347-55. DOI: 10.1016/j.ygeno.2007.12.007. View

11.

Cock P, Antao T, Chang J, Chapman B, Cox C, Dalke A . Biopython: freely available Python tools for computational molecular biology and bioinformatics. Bioinformatics. 2009; 25(11):1422-3. PMC: 2682512. DOI: 10.1093/bioinformatics/btp163. View

12.

Fleishman S, Whitehead T, Ekiert D, Dreyfus C, Corn J, Strauch E . Computational design of proteins targeting the conserved stem region of influenza hemagglutinin. Science. 2011; 332(6031):816-21. PMC: 3164876. DOI: 10.1126/science.1202617. View

13.

David A, Razali R, Wass M, Sternberg M . Protein-protein interaction sites are hot spots for disease-associated nonsynonymous SNPs. Hum Mutat. 2011; 33(2):359-63. DOI: 10.1002/humu.21656. View

14.

Whitehead T, Chevalier A, Song Y, Dreyfus C, Fleishman S, De Mattos C . Optimization of affinity, specificity and function of designed influenza inhibitors using deep sequencing. Nat Biotechnol. 2012; 30(6):543-8. PMC: 3638900. DOI: 10.1038/nbt.2214. View

15.

Moal I, Fernandez-Recio J . SKEMPI: a Structural Kinetic and Energetic database of Mutant Protein Interactions and its use in empirical models. Bioinformatics. 2012; 28(20):2600-7. DOI: 10.1093/bioinformatics/bts489. View

16.

Thiltgen G, Goldstein R . Assessing predictors of changes in protein stability upon mutation using self-consistency. PLoS One. 2012; 7(10):e46084. PMC: 3483175. DOI: 10.1371/journal.pone.0046084. View

17.

Dehouck Y, Kwasigroch J, Rooman M, Gilis D . BeAtMuSiC: Prediction of changes in protein-protein binding affinity on mutations. Nucleic Acids Res. 2013; 41(Web Server issue):W333-9. PMC: 3692068. DOI: 10.1093/nar/gkt450. View

18.

Pires D, Ascher D, Blundell T . mCSM: predicting the effects of mutations in proteins using graph-based signatures. Bioinformatics. 2013; 30(3):335-42. PMC: 3904523. DOI: 10.1093/bioinformatics/btt691. View

19.

Ascher D, Wielens J, Nero T, Doughty L, Morton C, Parker M . Potent hepatitis C inhibitors bind directly to NS5A and reduce its affinity for RNA. Sci Rep. 2014; 4:4765. PMC: 3996483. DOI: 10.1038/srep04765. View

20.

Pires D, Ascher D, Blundell T . DUET: a server for predicting effects of mutations on protein stability using an integrated computational approach. Nucleic Acids Res. 2014; 42(Web Server issue):W314-9. PMC: 4086143. DOI: 10.1093/nar/gku411. View