Abstract
Protein-protein interactions play crucial and subtle roles in many biological processes and modifications of their fine mechanisms generally result in severe diseases. Peptide derivatives are very promising therapeutic agents for modulating protein-protein associations with sizes and specificities between those of small compounds and antibodies. For the same reasons, rational design of peptide-based inhibitors naturally borrows and combines computational methods from both protein-ligand and protein-protein research fields. In this chapter, we aim to provide an overview of computational tools and approaches used for identifying and optimizing peptides that target protein-protein interfaces with high affinity and specificity. We hope that this review will help to implement appropriate in silico strategies for peptide-based drug design that builds on available information for the systems of interest.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Ryan DP, Matthews JM (2005) Protein-protein interactions in human disease. Curr Opin Struct Biol 15:441–446
Milroy L-G, Grossmann TN, Hennig S, Brunsveld L, Ottmann C (2014) Modulators of protein–protein interactions. Chem Rev 114:4695–4748
Archakov AI, Govorun VM, Dubanov AV, Ivanov YD, Veselovsky AV, Lewi P, Janssen P (2003) Protein-protein interactions as a target for drugs in proteomics. Proteomics 3:380–391
Sheng C, Dong G, Miao Z, Zhang W, Wang W (2015) State-of-the-art strategies for targeting protein–protein interactions by small-molecule inhibitors. Chem Soc Rev 44:8238–8259
Modell AE, Blosser SL, Arora PS (2016) Systematic targeting of protein–protein interactions. Trends Pharmacolog Sci 37:702–713
Wichapong K, Poelman H, Ercig B, Hrdinova J, Liu X, Lutgens E, Nicolaes GA (2019) Rational modulator design by exploitation of protein–protein complex structures. Future Med Chem 11:1015–1033
Yugandhar K, Gromiha MM (2016) Analysis of protein-protein interaction networks based on binding affinity. Current Protein Peptide Sci 17:72–81
Nevola L, Giralt E (2015) Modulating protein–protein interactions: the potential of peptides. Chem Commun 51:3302–3315
Cunningham AD, Qvit N, Mochly-Rosen D (2017) Peptides and peptidomimetics as regulators of protein–protein interactions. Current Opin Struct Biol 44:59–66
Fosgerau K, Hoffmann T (2015) Peptide therapeutics: current status and future directions. Drug Discovery Today 20:122–128
Cereto-Massagué A, Ojeda MJ, Valls C, Mulero M, Garcia-Vallvé S, Pujadas G (2015) Molecular fingerprint similarity search in virtual screening. Methods 71:58–63
Kaserer T, Beck K, Akram M, Odermatt A, Schuster D (2015) Pharmacophore models and pharmacophore-based virtual screening: concepts and applications exemplified on hydroxysteroid dehydrogenases. Molecules 20:22799–22832
Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ (1990) Basic local alignment search tool. J Mol Biol 215:403–410
Zhang R, Ou H-Y, Zhang C-T (2004) DEG: a database of essential genes. Nucleic Acids Res 32:D271–D272
Rey S, Acab M, Gardy JL, Laird MR, deFays K, Lambert C, Brinkman FSL (2005) PSORTdb: a protein subcellular localization database for bacteria. Nucleic Acids Res 33:D164–D168
Gawade P, Ghosh P (2018) Genomics driven approach for identification of novel therapeutic targets in Salmonella enterica. Gene 668:211–220
Pirtskhalava M, Gabrielian A, Cruz P, Griggs HL, Squires RB, Hurt DE, Grigolava M, Chubinidze M, Gogoladze G, Vishnepolsky B, Alekseev V, Rosenthal A, Tartakovsky M (2016) DBAASP v.2: an enhanced database of structure and antimicrobial/cytotoxic activity of natural and synthetic peptides. Nucleic Acids Res 44:D1104–D1112
Minkiewicz P, Iwaniak A, Darewicz M (2019) BIOPEP-UWM database of bioactive peptides: current opportunities. Int J Mol Sci 20:5978
Chou K-C (2001) Prediction of protein cellular attributes using pseudo-amino acid composition. Proteins: Struct Funct Genet 43:246–255
Rao HB, Zhu F, Yang GB, Li ZR, Chen YZ (2011) Update of PROFEAT: a web server for computing structural and physicochemical features of proteins and peptides from amino acid sequence. Nucleic Acids Res 39:W385–W390
Chen W, Ding H, Feng P, Lin H, Chou K-C (2016) iACP: a sequence-based tool for identifying anticancer peptides. Oncotarget 7:16895–16909
Xu L, Liang G, Wang L, Liao C (2018) A Novel hybrid sequence-based model for identifying anticancer peptides. Genes 9:158
Wei L, Zhou C, Chen H, Song J, Su R (2018) ACPred-FL: a sequence-based predictor using effective feature representation to improve the prediction of anti-cancer peptides. Bioinformatics 34:4007–4016
Blanco JL, Porto-Pazos AB, Pazos A, Fernandez-Lozano C (2018) Prediction of high anti-angiogenic activity peptides in silico using a generalized linear model and feature selection. Sci Rep 8:15688
Laengsri V, Nantasenamat C, Schaduangrat N, Nuchnoi P, Prachayasittikul V, Shoombuatong W (2019) TargetAntiAngio: a sequence-based tool for the prediction and analysis of anti-angiogenic peptides. Int J Mol Sci 20:2950
Bhadra P, Yan J, Li J, Fong S, Siu SWI (2018) AmPEP: sequence-based prediction of antimicrobial peptides using distribution patterns of amino acid properties and random forest. Sci Rep 8:1697
Khosravian M, Kazemi Faramarzi F, Mohammad Beigi M, Behbahani M, Mohabatkar H (2013) Predicting antibacterial peptides by the concept of Chou’s Pseudo-amino acid composition and machine learning methods. Protein Peptide Lett 20:180–186
Schaduangrat N, Nantasenamat C, Prachayasittikul V, Shoombuatong W (2019) Meta-iAVP: a sequence-based meta-predictor for improving the prediction of antiviral peptides using effective feature representation. Int J Mol Sci 20:5743
Tung C-W, Ziehm M, Kämper A, Kohlbacher O, Ho S-Y (2011) POPISK: T-cell reactivity prediction using support vector machines and string kernels. BMC Bioinf 12:446
Jorgensen KW, Rasmussen M, Buus S, Nielsen M (2014) NetMHCstab - predicting stability of peptide-MHC-I complexes; impacts for cytotoxic T lymphocyte epitope discovery. Immunology 141:18–26
Vita R, Mahajan S, Overton JA, Dhanda SK, Martini S, Cantrell, JR, Wheeler DK, Sette A, Peters B (2019) The immune epitope database (IEDB): 2018 update. Nucleic Acids Res 47:D339–D343
Gupta S, Mittal P, Madhu MK, Sharma VK (2017) IL17eScan: a tool for the identification of peptides inducing IL-17 response. Front Immunol 8:1430
Manavalan B, Shin TH, Kim MO, Lee G (2018) AIPpred: sequence-based prediction of anti-inflammatory peptides using random forest. Front Pharmacol 9:276
Wei L, Zhou C, Su R, Zou Q (2019) PEPred-Suite: improved and robust prediction of therapeutic peptides using adaptive feature representation learning. Bioinf 35:4272–4280
Tang H, Su, Z.-D., Wei, H.-H., Chen W, Lin H (2016) Prediction of cell-penetrating peptides with feature selection techniques. Biochem Biophys Res Commun 477:150–154
Wei L, Xing P, Su R, Shi G, Ma ZS, Zou Q (2017) CPPred-RF: a sequence-based predictor for identifying cell-penetrating peptides and their uptake efficiency. J Proteome Res 16:2044–2053
Pandey P, Patel V, George NV, Mallajosyula SS (2018) KELM-CPPpred: Kernel extreme learning machine based prediction model for cell-penetrating peptides. J Proteome Res 17:3214–3222
Arif M, Ahmad S, Ali F, Fang G, Li M, Yu, D-J (2020) TargetCPP: accurate prediction of cell-penetrating peptides from optimized multi-scale features using gradient boost decision tree. J Comput Aided Mol Des 34:841–856
Chen M, Ju C JT, Zhou G, Chen X, Zhang T, Chang K-W, Zaniolo C, Wang W (2019) Multifaceted protein–protein interaction prediction based on Siamese residual RCNN. Bioinformatics 35:i305–i314
Hashemifar S, Neyshabur B, Khan AA, Xu J (2018) Predicting protein-protein interactions through sequence-based deep learning. Bioinformatics 34:i802–i810
Tran L, Hamp T, Rost B (2018) ProfPPIdb: Pairs of physical protein-protein interactions predicted for entire proteomes. PLOS One 13:e0199988
Romero-Molina S, Ruiz-Blanco YB, Harms M, Münch J, Sanchez-Garcia E (2019) PPI-detect: a support vector machine model for sequence-based prediction of protein-protein interactions: PPI-Detect: a support vector machine model for sequence-based prediction of protein-protein interactions. J Comput Chem 40:1233–1242
Eid F-E, ElHefnawi M, Heath LS (2016) DeNovo: virus-host sequence-based protein–protein interaction prediction. Bioinf 32:1144–1150
Lian X, Yang S, Li H, Fu C, Zhang Z (2019) Machine-learning-based predictor of human-bacteria protein-protein interactions by incorporating comprehensive host-network properties. J Proteome Res 18:2195–2205
Kösesoy I, Gök M, Öz C (2019) A new sequence based encoding for prediction of host–pathogen protein interactions. Comput Biol Chem 78:170–177
Tan S-H, Hugo W, Sung, W-K, Ng S-K (2006) A correlated motif approach for finding short linear motifs from protein interaction networks. BMC Bioinf 7:502
Leung HC-M, Siu M-H, Yiu S-M, Chin FY-L, Sung KW-K (2009) Clustering-based approach for predicting motif pairs from protein interaction data. J Bioinf Comput Biol 07:701–716
Hugo W, Ng S-K, Sung W-K (2011) D-SLIMMER: domain-SLiM interaction motifs miner for sequence based protein-protein interaction data. J Proteome Res 10:5285–5295
Disfani FM, Hsu W-L, Mizianty MJ, Oldfield CJ, Xue B, Dunker AK, Uversky VN, Kurgan L (2012) MoRFpred, a computational tool for sequence-based prediction and characterization of short disorder-to-order transitioning binding regions in proteins. Bioinformatics 28:i75–i83
Malhis N, Gsponer J (2015) Computational identification of MoRFs in protein sequences. Bioinformatics 31:1738–1744
He H, Zhao J, Sun G (2019) Computational prediction of MoRFs based on protein sequences and minimax probability machine. BMC Bioinf 20:529
Chen JR, Chang BH, Allen JE, Stiffler MA, MacBeath G (2008) Predicting PDZ domain–peptide interactions from primary sequences. Nat Biotechnol 26:1041–1045
Reimand J, Hui S, Jain S, Law B, Bader GD (2012) Domain-mediated protein interaction prediction: from genome to network. FEBS Lett 586:2751–2763
Sarkar D, Jana T, Saha S (2018) LMDIPred: a web-server for prediction of linear peptide sequences binding to SH3, WW and PDZ domains. PLOS One 13:e0200430
Xue LC, Dobbs D, Honavar V (2011) HomPPI: a class of sequence homology based protein-protein interface prediction methods. BMC Bioinf 12:244
Garcia-Garcia J, Valls-Comamala V, Guney E, Andreu D, Muñoz FJ, Fernandez-Fuentes N, Oliva B (2017) iFrag: a protein–protein interface prediction server based on sequence fragments. J Mol Biol 429:382–389
Dhole K, Singh G, Pai PP, Mondal S (2014) Sequence-based prediction of protein–protein interaction sites with L1-logreg classifier. J Theoret Biol 348:47–54
Jia J, Liu Z, Xiao X, Liu B, Chou, K-C (2016) iPPBS-Opt: a sequence-based ensemble classifier for identifying protein-protein binding sites by optimizing imbalanced training datasets. Molecules 21:95
Hou Q, De Geest PFG, Griffioen CJ, Abeln S, Heringa J, Feenstra KA (2019) SeRenDIP: SEquential REmasteriNg to DerIve profiles for fast and accurate predictions of PPI interface positions. Bioinformatics 35:4794–4796
Afsar Minhas FuA, Geiss BJ, Ben-Hur A (2014) PAIRpred: partner-specific prediction of interacting residues from sequence and structure: interface prediction using PAIRpred. Proteins: Struct Funct Bioinf 82:1142–1155
Meyer MJ, Beltrán JF, Liang S, Fragoza R, Rumack A, Liang J, Wei X, Yu H (2018) Interactome INSIDER: a structural interactome browser for genomic studies. Nat Methods 15:107–114
Sanchez-Garcia R, Sorzano COS, Carazo JM, Segura J (2019) BIPSPI: a method for the prediction of partner-specific protein-protein interfaces. Bioinf 35:470–477
Taherzadeh G, Yang Y, Zhang T, Liew AW-C, Zhou Y (2016) Sequence-based prediction of protein-peptide binding sites using support vector machine. J Comput Chem 37:1223–1229
Zhao Z, Peng Z, Yang J (2018) Improving sequence-based prediction of protein–peptide binding residues by introducing intrinsic disorder and a consensus method. J Chem Inf Model 58:1459–1468
Dosztányi Z, Csizmok V, Tompa P, Simon I (2005) IUPred: web server for the prediction of intrinsically unstructured regions of proteins based on estimated energy content. Bioinformatics 21:3433–3434
Yugandhar K, Gromiha MM (2014) Feature selection and classification of protein–protein complexes based on their binding affinities using machine learning approaches. Proteins: Struct Funct Bioinf 82:2088–2096
Srinivasulu Y, Wang, J-R, Hsu K-T, Tsai M-J, Charoenkwan P, Huang W-L, Huang H-L, Ho S-Y (2015) Characterizing informative sequence descriptors and predicting binding affinities of heterodimeric protein complexes. BMC Bioinf 16:S14
Shao X, Tan CSH, Voss C, Li SSC, Deng N, Bader GD (2011) A regression framework incorporating quantitative and negative interaction data improves quantitative prediction of PDZ domain–peptide interaction from primary sequence. Bioinformatics 27:383–390
Moal IH, Agius R, Bates PA (2011) Protein–protein binding affinity prediction on a diverse set of structures. Bioinformatics 27:3002–3009
Luo J, Guo Y, Zhong Y, Ma D, Li W, Li M (2014) A functional feature analysis on diverse protein–protein interactions: application for the prediction of binding affinity. J Comput Aided Mol Design 28:619–629.
Kamisetty H, Ghosh B, Langmead CJ, Bailey-Kellogg C (2015) Learning sequence determinants of protein:protein interaction specificity with sparse graphical models. J Comput Biol 22:474–486
Jemimah S, Yugandhar K, Michael Gromiha M (2017) PROXiMATE: a database of mutant protein–protein complex thermodynamics and kinetics. Bioinf 33:2787–2788
Jankauskaitė J, Jiménez-García B, Dapkūnas J, Fernández-Recio J, Moal IH (2019) SKEMPI 2.0: an updated benchmark of changes in protein–protein binding energy, kinetics and thermodynamics upon mutation. Bioinformatics 35:462–469
Geng C, Vangone A, Folkers GE, Xue LC, Bonvin AMJJ (2019) iSEE: Interface structure, evolution, and energy-based machine learning predictor of binding affinity changes upon mutations. Proteins: Struct Funct Bioinf 87:110–119
Rodrigues CHM, Myung Y, Pires DEV, Ascher DB (2019) mCSM-PPI2: predicting the effects of mutations on protein–protein interactions. Nucleic Acids Res 47:W338–W344
Zhang N, Chen Y, Lu H, Zhao F, Alvarez RV, Goncearenco A, Panchenko AR, Li M (2020) MutaBind2: predicting the impacts of single and multiple mutations on protein-protein interactions. iScience 23:100939
Jemimah S, Sekijima M, Gromiha MM (2019) ProAffiMuSeq: sequence-based method to predict the binding free energy change of protein–protein complexes upon mutation using functional classification. Bioinformatics 36:1725–1730
Li G, Pahari S, Krishna Murthy A, Liang S, Fragoza R, Yu H, Alexov E (2020) SAAMBE-SEQ: a sequence-based method for predicting mutation effect on protein-protein binding affinity. Bioinformatics 37:btaa761
Massa SM, Xie Y, Longo FM (2003) Alzheimer’s therapeutics. J Mol Neurosci 20:323–326
Parthasarathi L, Casey F, Stein A, Aloy P, Shields DC (2008) Approved drug mimics of short peptide ligands from protein interaction motifs. J Chem Inf Model 48:1943–1948
Fayaz SM, Rajanikant GK (2015) Modelling the molecular mechanism of protein–protein interactions and their inhibition: CypD–p53 case study. Mol Diversity 19:931–943
Caporuscio F, Tafi A, González E, Manetti F, Esté JA, Botta, M (2009) A dynamic target-based pharmacophoric model mapping the CD4 binding site on HIV-1 gp120 to identify new inhibitors of gp120–CD4 protein–protein interactions. Bioorganic Med Chem Lett 19:6087–6091
Hall PR, Leitão A, Ye C, Kilpatrick K, Hjelle B, Oprea TI, Larson RS (2010) Small molecule inhibitors of hantavirus infection. Bioorganic Med Chem Lett 20:7085–7091
Pihan E, Delgadillo RF, Tonkin ML, Pugnière M, Lebrun M, Boulanger MJ, Douguet D (2015) Computational and biophysical approaches to protein–protein interaction inhibition of Plasmodium falciparum AMA1/RON2 complex. J Comput Aided Mol Design 29:525–539
Jesus Perez de Vega M, Martin-Martinez M, Gonzalez-Muniz R (2007) Modulation of protein-protein interactions by stabilizing/mimicking protein secondary structure elements. Current Topics Med Chem 7:33–62
Klein M (2017) Stabilized helical peptides: overview of the technologies and its impact on drug discovery. Expert Opin Drug Disc 12:1117–1125
Guarracino DA, Riordan JA, Barreto GM, Oldfield AL, Kouba CM, Agrinsoni D (2019) Macrocyclic control in Helix Mimetics. Chem Rev 119:9915–9949
Khakshoor O, Nowick JS (2008) Artificial β-sheets: chemical models of β-sheets. Current Opin Chem Biol 12:722–729
Laxio Arenas J, Kaffy J, Ongeri S (2019) Peptides and peptidomimetics as inhibitors of protein–protein interactions involving β-sheet secondary structures. Current Opin Chem Biol 52:157–167
Tanaka M (2007) Design and synthesis of chiral α,α-disubstituted amino acids and conformational study of their oligopeptides. Chem Pharmaceut Bull 55:349–358
Chatterjee J, Rechenmacher F, Kessler H (2013) N-Methylation of peptides and proteins: an important element for modulating biological functions. Angew Chem Int Edition 52:254–269
Sarnowski MP, Pedretty KP, Giddings N, Woodcock HL, Del Valle JR (2018) Synthesis and β-sheet propensity of constrained N-amino peptides. Bioorganic Med Chem 26:1162–1166
Matthes D, Groot BLd (2009) Secondary structure propensities in peptide folding simulations: a systematic comparison of molecular mechanics interaction schemes. Biophys J 97:599–608
Rauscher S, Gapsys V, Gajda MJ, Zweckstetter M, de Groot BL, Grubmüller H (2015) Structural ensembles of intrinsically disordered proteins depend strongly on force field: a comparison to experiment. J Chem Theory Comput 11:5513–5524
Chan-Yao-Chong M, Deville C, Pinet L, van Heijenoort C, Durand D, Ha-Duong T (2019) Structural characterization of N-WASP domain V using MD simulations with NMR and SAXS data. Biophys J 116:1216–1227
Sugita Y, Okamoto Y (1999) Replica-exchange molecular dynamics method for protein folding. Chem Phys Lett 314:141–151
Laio A and Parrinello M (2002). Escaping free-energy minima. Proc Natl Acad Sci 99:12562–12566
Joseph TL, Lane DP, Verma CS (2012) Stapled BH3 peptides against MCL-1: mechanism and design using atomistic simulations. PLOS One 7:e43985
Damas JM, Filipe LC, Campos SR, Lousa D, Victor BL, Baptista AM, Soares CM (2013) Predicting the thermodynamics and kinetics of Helix formation in a cyclic peptide model. J Chem Theory Comput 9:5148–5157
Cornillie SP, Bruno BJ, Lim CS, Cheatham TE (2018) Computational modeling of stapled peptides toward a treatment strategy for CML and broader implications in the design of lengthy peptide therapeutics. J Phys Chem B 122:3864–3875
Lama D, Quah ST, Verma CS, Lakshminarayanan R, Beuerman RW, Lane DP, Brown CJ (2013) Rational optimization of conformational effects induced by hydrocarbon staples in peptides and their binding interfaces. Sci Rep 3:3451
Zhu J, Wei S, Huang L, Zhao Q, Zhu H, Zhang A (2020) Molecular modeling and rational design of hydrocarbon-stapled/halogenated helical peptides targeting CETP self-binding site: Therapeutic implication for atherosclerosis. J Mol Graph Modell 94:107455
Tan YS, Lane DP, Verma CS (2016) Stapled peptide design: principles and roles of computation. Drug Discovery Today 21:1642–1653
Spitaleri A, Ghitti M, Mari S, Alberici L, Traversari C, Rizzardi G-P, Musco G (2011) Use of metadynamics in the design of isoDGR-based αvβ3 antagonists to fine-tune the conformational ensemble. Ang Chem Int Edition 50:1832–1836
Yedvabny E, Nerenberg PS, So C, Head-Gordon T (2015) Disordered structural ensembles of vasopressin and oxytocin and their mutants. J Phys Chem B 119:896–905
Yu H, Lin, Y-S (2015) Toward structure prediction of cyclic peptides. Phys Chem Chem Phys 17:4210–4219
McHugh SM, Rogers JR, Solomon SA, Yu H, Lin Y-S (2016) Computational methods to design cyclic peptides. Current Opin Chem Biol 34:95–102
Quartararo JS, Eshelman MR, Peraro L, Yu H, Baleja JD, Lin Y-S, Kritzer JA (2014) A bicyclic peptide scaffold promotes phosphotyrosine mimicry and cellular uptake. Bioorganic Med Chem 22:6387–6391
Razavi AM, Wuest WM, Voelz VA (2014) Computational screening and selection of cyclic peptide hairpin mimetics by molecular simulation and kinetic network models. J Chem Inf Model 54:1425–1432
Wakefield AE, Wuest WM, Voelz VA (2015) Molecular simulation of conformational pre-organization in cyclic RGD peptides. J Chem Inf Model 55:806–813
Est CB, Mangrolia P, Murphy RM (2019) ROSETTA-informed design of structurally stabilized cyclic anti-amyloid peptides. Protein Eng Design Select 32:47–57
Paissoni C, Ghitti M, Belvisi L, Spitaleri A, Musco G (2015) Metadynamics simulations rationalise the conformational effects induced by N-methylation of RGD cyclic hexapeptides. Chem A Europ J 21:14165–14170
Slough DP, Yu H, McHugh SM, Lin Y-S (2017) Toward accurately modeling N-methylated cyclic peptides. Phys Chem Chem Phys 19:5377–5388
Lensink MF, Velankar S, Wodak SJ (2017) Modeling protein-protein and protein-peptide complexes: CAPRI 6th edition: modeling protein-protein and protein-peptide complexes. Proteins Struct Funct Bioinf 85:359–377
Gowthaman R, Miller SA, Rogers S, Khowsathit J, Lan L, Bai N, Johnson DK, Liu C, Xu L, Anbanandam A, Aubé J, Roy A, Karanicolas J (2016) DARC: mapping surface topography by ray-casting for effective virtual screening at protein interaction sites. J Med Chem 59:4152–4170
Binkowski TA, Naghibzadeh S, Liang J (2003) CASTp: computed atlas of surface topography of proteins. Nucleic Acids Res 31:3352–3355
Le Guilloux V, Schmidtke P, Tuffery P (2009) Fpocket: an open source platform for ligand pocket detection. BMC Bioinf 10:168
Guo Z, Thorarensen A, Che J, Xing L (2016) Target the more druggable protein states in a highly dynamic protein–protein interaction system. J Chem Inf Model 56:35–45
Guo Z, Li B, Dzubiella J, Cheng L-T, McCammon JA, Che J (2013) Evaluation of hydration free energy by level-set variational implicit-solvent model with coulomb-field approximation. J Chem Theory Comput 9:1778–1787
Liu S, Liu C, Deng L (2018) Machine learning approaches for protein–protein interaction hot spot prediction: progress and comparative assessment. Molecules 23:2535
Tuncbag N, Gursoy A, Keskin O (2009) Identification of computational hot spots in protein interfaces: combining solvent accessibility and inter-residue potentials improves the accuracy. Bioinf 25:1513–1520
Xia J-F, Zhao X-M, Song J, Huang D-S (2010) APIS: accurate prediction of hot spots in protein interfaces by combining protrusion index with solvent accessibility. BMC Bioinf 11:174
Wang L, Liu Z-P, Zhang X-S, Chen L (2012) Prediction of hot spots in protein interfaces using a random forest model with hybrid features. Protein Eng Design Select 25:119–126
Deng L, Guan J, Wei X, Yi Y, Zhang QC, Zhou S (2013) Boosting prediction performance of protein-protein interaction hot spots by using structural neighborhood properties. J Comput Biol 20:878–891
Qiao Y, Xiong Y, Gao H, Zhu X, Chen P (2018) Protein-protein interface hot spots prediction based on a hybrid feature selection strategy. BMC Bioinf 19:14
Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) Development and validation of a genetic algorithm for flexible docking11Edited by F. E. Cohen. J Mol Biol 267:727–748
Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455–461
Wang L, Hou Y, Quan H, Xu W, Bao Y, Li Y, Fu Y, Zou S (2013) A compound-based computational approach for the accurate determination of hot spots. Protein Sci 22:1060–1070
Kulp JL, Kulp JL, Pompliano DL, Guarnieri F (2011) Diverse fragment clustering and water exclusion identify protein hot spots. J Amer Chem Soc 133:10740–10743
Kulp JL, Cloudsdale IS, Kulp JL, Guarnieri F (2017) Hot-spot identification on a broad class of proteins and RNA suggest unifying principles of molecular recognition. PLOS One 12:e0183327
Cunningham BC, Wells JA (1989) High-resolution epitope mapping of hGH-receptor interactions by alanine-scanning mutagenesis. Science 244:1081–1085
Barlow KA, Ó Conchúir S, Thompson S, Suresh P, Lucas JE, Heinonen M, Kortemme T (2018) Flex ddG: Rosetta ensemble-based estimation of changes in protein-protein binding affinity upon mutation. J Phys Chem B 122:5389–5399
Ibarra AA, Bartlett GJ, Hegedüs Z, Dutt S, Hobor F, Horner KA, Hetherington K, Spence K, Nelson A, Edwards TA, Woolfson DN, Sessions RB, Wilson AJ (2019) Predicting and experimentally validating hot-spot residues at protein–protein interfaces. ACS Chem Biol 14:2252–2263
Martins SA, Perez M AS, Moreira IS, Sousa SF, Ramos MJ, Fernandes PA (2013) Computational alanine scanning mutagenesis: MM-PBSA vs TI. J Chem Theory Comput 9:1311–1319
Yang XQ, Liu JY, Li XC, Chen MH, Zhang YL (2014) Key amino acid associated with acephate detoxification by cydia pomonella carboxylesterase based on molecular dynamics with alanine scanning and site-directed mutagenesis. J Chem Inf Model 54:1356–1370
Dapiaggi F, Pieraccini S, Sironi M (2015) In silico study of VP35 inhibitors: from computational alanine scanning to essential dynamics. Mol BioSyst 11:2152–2157
He L, Bao J, Yang Y, Dong S, Zhang L, Qi Y, Zhang JZH (2019) Study of SHMT2 inhibitors and their binding mechanism by computational alanine scanning. J Chem Inf Model 59:3871–3878
Laurini E, Marson D, Aulic S, Fermeglia M, Pricl S (2020) Computational Alanine scanning and structural analysis of the SARS-CoV-2 Spike protein/angiotensin-converting enzyme 2 complex. ACS Nano 14:11821–11830
Zhao J, Yin B, Sun H, Pang L, Chen J (2020) Identifying hot spots of inhibitor-CDK2 bindings by computational alanine scanning. Chem Phys Lett 747:137329
Chen R, Li L, Weng Z (2003) ZDOCK: an initial-stage protein-docking algorithm. Proteins 52:80–87
Baspinar A, Cukuroglu E, Nussinov R, Keskin O, Gursoy A (2014) PRISM: a web server and repository for prediction of protein–protein interactions and modeling their 3D complexes. Nucleic Acids Res 42:W285–W289
Cheng TM-K, Blundell TL, Fernandez-Recio J (2007) pyDock: electrostatics and desolvation for effective scoring of rigid-body protein-protein docking. Proteins 68:503–515
Degryse B, Fernandez-Recio J, Citro V, Blasi F, Cubellis MV (2008) In silico docking of urokinase plasminogen activator and integrins. BMC Bioinf 9:S8
Lee H, Heo L, Lee MS, Seok C (2015) GalaxyPepDock: a protein-peptide docking tool based on interaction similarity and energy optimization. Nucleic Acids Res 43:W431–435
Yan Y, Wen Z, Wang X, Huang S-Y (2017) Addressing recent docking challenges: a hybrid strategy to integrate template-based and free protein-protein docking. Proteins Struct Funct Bioinf 85:497–512
Johansson-Åkhe I, Mirabello C, Wallner B (2020) InterPep2: global peptide–protein docking using interaction surface templates. Bioinformatics 36:2458–2465
Schindler C, de Vries S, Zacharias M (2015) Fully blind peptide-protein docking with pepATTRACT. Structure 23:1507–1515
Yan C, Xu X, Zou X (2016) Fully blind docking at the atomic level for protein-peptide complex structure prediction. Structure 24:1842–1853
Alam N, Goldstein O, Xia B, Porter KA, Kozakov D, Schueler-Furman O (2017) High-resolution global peptide-protein docking using fragments-based PIPER-FlexPepDock. PLOS Comput Biol 13:e1005905
Zhou P, Jin B, Li H, Huang S-Y (2018) HPEPDOCK: a web server for blind peptide–protein docking based on a hierarchical algorithm. Nucleic Acids Res 46:W443–W450
Raveh B, London N, Schueler-Furman O (2010) Sub-angstrom modeling of complexes between flexible peptides and globular proteins. Proteins 78:2029–2040
Ben-Shimon A, Niv MY (2015). AnchorDock: blind and flexible anchor-driven peptide docking. Structure 23:929–940
Kurcinski M, Jamroz M, Blaszczyk M, Kolinski A, Kmiecik S (2015) CABS-dock web server for the flexible docking of peptides to proteins without prior knowledge of the binding site. Nucleic Acids Res 43:W419–W424
Antunes DA, Moll M, Devaurs D, Jackson KR, Lizée G, Kavraki LE (2017) DINC 2.0: a new protein-peptide docking webserver using an incremental approach. Cancer Res 77:e55–e57
Peterson LX, Roy A, Christoffer C, Terashi G, Kihara D (2017) Modeling disordered protein interactions from biophysical principles. PLOS Comput Biol 13:e1005485
London N, Raveh B, Movshovitz-Attias D, Schueler-Furman O (2010) Can self-inhibitory peptides be derived from the interfaces of globular protein-protein interactions? Proteins 78:3140–3149
London N, Raveh B, Schueler-Furman O (2013) Druggable protein-protein interactions? from hot spots to hot segments. Current Opin Chem Biol 17:952–959
Nomme J, Takizawa Y, Martinez SF, Renodon-Cornière A, Fleury F, Weigel P, Yamamoto K-i, Kurumizaka H, Takahashi M (2008) Inhibition of filament formation of human Rad51 protein by a small peptide derived from the BRC-motif of the BRCA2 protein. Genes Cells 13:471–481
Nomme J, Renodon-Cornière A, Asanomi Y, Sakaguchi K, Stasiak AZ, Stasiak A, Norden B, Tran V, Takahashi M (2010) Design of potent inhibitors of human RAD51 recombinase based on BRC motifs of BRCA2 protein: modeling and experimental validation of a chimera peptide. J Med Chem 53:5782–5791
Jafary F, Ganjalikhany MR, Moradi A, Hemati M, Jafari S (2019) Novel peptide inhibitors for lactate dehydrogenase a (LDHA): a survey to inhibit ldha activity via disruption of protein-protein interaction. Sci Rep 9:4686
Gavenonis J, Jonas NE, Kritzer JA (2014) Potential C-terminal-domain inhibitors of heat shock protein 90 derived from a C-terminal peptide helix. Bioorganic Med Chem 22:3989–3993
Bopp B, Ciglia E, Ouald-Chaib A, Groth G, Gohlke H, Jose J (2016) Design and biological testing of peptidic dimerization inhibitors of human Hsp90 that target the C-terminal domain. Biochim et Biophys Acta 1860:1043–1055
Sedan Y, Marcu O, Lyskov S, Schueler-Furman O (2016) Peptiderive server: derive peptide inhibitors from protein–protein interactions. Nucleic Acids Res 44:W536–W541
Horita S, Nomura Y, Sato Y, Shimamura T, Iwata S, Nomura N (2016) High-resolution crystal structure of the therapeutic antibody pembrolizumab bound to the human PD-1. Sci Rep 6:35297
Li D, Song H, Mei H, Fang E, Wang X, Yang F, Li H, Chen Y, Huang K, Zheng L, Tong Q (2018) Armadillo repeat containing 12 promotes neuroblastoma progression through interaction with retinoblastoma binding protein 4. Nat Commun 9:2829
Tarsia C, Danielli A, Florini F, Cinelli P, Ciurli S, Zambelli B (2018) Targeting Helicobacter pylori urease activity and maturation: in-cell high-throughput approach for drug discovery. Bioch et Biophys Acta 1862:2245–2253
Geppert T, Bauer S, Hiss JA, Conrad E, Reutlinger M, Schneider P, Weisel M, Pfeiffer B, Altmann K-H, Waibler Z, Schneider G (2012) Immunosuppressive small molecule discovered by structure-based virtual screening for inhibitors of protein–protein interactions. Angew Chem Int Edition 51:258–261
Johnson DK, Karanicolas J (2016) Ultra-high-throughput structure-based virtual screening for small-molecule inhibitors of protein–protein interactions. J Chem Inf Model 56:399–411
Koes DR, Dömling A, Camacho CJ (2018) AnchorQuery: rapid online virtual screening for small-molecule protein–protein interaction inhibitors. Protein Sci 27:229–232
Wu H, Liu Y, Guo M, Xie J, Jiang X (2014) A virtual screening method for inhibitory peptides of angiotensin i–converting enzyme J Food Sci 79:C1635–C1642
Yu Z, Fan Y, Zhao W, Ding L, Li J, Liu J (2018) Novel angiotensin-converting enzyme inhibitory peptides derived from oncorhynchus mykiss nebulin: virtual screening and in silico molecular docking study. J Food Sci 83:2375–2383
Yu Z, Kan R, Wu S, Guo H, Zhao W, Ding L, Zheng F, and Liu, J. (2020). Xanthine oxidase inhibitory peptides derived from tuna protein: virtual screening, inhibitory activity, and molecular mechanisms. J Sci Food Agric
Kim DE, Chivian D, Baker D (2004) Protein structure prediction and analysis using the Robetta server. Nucleic Acids Res 32:W526–W531
Duffy FJ, Verniere M, Devocelle M, Bernard E, Shields DC, Chubb AJ (2011) CycloPs: generating virtual libraries of cyclized and constrained peptides including nonnatural amino acids. J Chem Inf Model 51:829–836
Huang P-S, Boyken SE, Baker D (2016) The coming of age of de novo protein design. Nature 537:320–327
Kortemme T, Joachimiak LA, Bullock AN, Schuler AD, Stoddard BL, Baker D (2004) Computational redesign of protein-protein interaction specificity. Nat Struct Mol Biol 11:371–379
Roberts KE, Cushing PR, Boisguerin P, Madden DR, Donald BR (2012) Computational design of a PDZ domain peptide inhibitor that rescues CFTR activity. PLOS Comput Biol 8:e1002477
Sharabi O, Shirian J, Shifman J (2013) Predicting affinity- and specificity-enhancing mutations at protein–protein interfaces. Biochem Soc Trans 41:1166–1169
Simonson T, Gaillard T, Mignon D, Schmidt am Busch M, Lopes A, Amara N, Polydorides S, Sedano A, Druart K, Archontis G (2013) Computational protein design: the Proteus software and selected applications. J Comput Chem 34:2472–2484
Frappier V, Jenson JM, Zhou J, Grigoryan G, Keating AE (2019) Tertiary structural motif sequence statistics enable facile prediction and design of peptides that bind anti-apoptotic Bfl-1 and Mcl-1. Structure 27:606–617.e5
Poole AM, Ranganathan R (2006) Knowledge-based potentials in protein design. Current Opin Struct Biol 16:508–513
Boas FE, Harbury PB (2007) Potential energy functions for protein design. Current Opin Struct Biol 17:199–204
Mackenzie CO, Zhou J, Grigoryan G (2016) Tertiary alphabet for the observable protein structural universe. Proc Natl Acad Sci 113:E7438–E7447
Zheng F, Zhang J, Grigoryan G (2015) Tertiary structural propensities reveal fundamental Sequence/structure relationships. Structure 23:961–971
Grigoryan G, Reinke AW, Keating AE (2009) Design of protein-interaction specificity gives selective bZIP-binding peptides. Nature 458:859–864
Chen TS, Reinke AW, Keating AE (2011) Design of peptide inhibitors that bind the bZIP Domain of Epstein–barr virus protein BZLF1 J Mol Biol 408:304–320
Smith CA, Kortemme T (2010) Structure-based prediction of the peptide sequence space recognized by natural and synthetic PDZ domains. J Mol Biol 402:460–474
Zheng F, Jewell H, Fitzpatrick J, Zhang J, Mierke DF, Grigoryan G (2015) Computational design of selective peptides to discriminate between similar PDZ domains in an oncogenic pathway. J Mol Biol 427:491–510
Sievers SA, Karanicolas J, Chang HW, Zhao A, Jiang L, Zirafi O, Stevens JT, Münch J, Baker D, Eisenberg D (2011) Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation. Nature 475:96–100
Zhang C, Shen Q, Tang B, Lai L (2013) Computational design of helical peptides targeting TNFα. Angew Chem Int Edition 52:11059–11062
Yang W, Zhang Q, Zhang C, Guo A, Wang Y, You H, Zhang X, Lai L (2019) Computational design and optimization of novel d-peptide TNFα inhibitors. FEBS Lett 593:1292–1302
Foight GW, Ryan JA, Gullá SV, Letai A, Keating AE (2014) Designed BH3 peptides with high affinity and specificity for targeting Mcl-1 in cells. ACS Chem Biol 9:1962–1968
Berger S, Procko E, Margineantu D, Lee EF, Shen BW, Zelter A, Silva D-A, Chawla K, Herold MJ, Garnier J-M, Johnson R, MacCoss MJ, Lessene G, Davis TN, Stayton PS, Stoddard BL, Fairlie WD, Hockenbery DM, Baker D (2016) Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer. eLife 5:e20352
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2022 The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Delaunay, M., Ha-Duong, T. (2022). Computational Tools and Strategies to Develop Peptide-Based Inhibitors of Protein-Protein Interactions. In: Simonson, T. (eds) Computational Peptide Science. Methods in Molecular Biology, vol 2405. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1855-4_11
Download citation
DOI: https://doi.org/10.1007/978-1-0716-1855-4_11
Published:
Publisher Name: Humana, New York, NY
Print ISBN: 978-1-0716-1854-7
Online ISBN: 978-1-0716-1855-4
eBook Packages: Springer Protocols