title: Characterizing changes in the rate of protein-protein dissociation upon interface mutation using hotspot energy and organization.
abstract: Predicting the effects of mutations on the kinetic rate constants of protein-protein interactions is central to both the modeling of complex diseases and the design of effective peptide drug inhibitors. However, while most studies have concentrated on the determination of association rate constants, dissociation rates have received less attention. In this work we take a novel approach by relating the changes in dissociation rates upon mutation to the energetics and architecture of hotspots and hotregions, by performing alanine scans pre- and post-mutation. From these scans, we design a set of descriptors that capture the change in hotspot energy and distribution. The method is benchmarked on 713 kinetically characterized mutations from the SKEMPI database. Our investigations show that, with the use of hotspot descriptors, energies from single-point alanine mutations may be used for the estimation of off-rate mutations to any residue type and also multi-point mutations. A number of machine learning models are built from a combination of molecular and hotspot descriptors, with the best models achieving a Pearson's Correlation Coefficient of 0.79 with experimental off-rates and a Matthew's Correlation Coefficient of 0.6 in the detection of rare stabilizing mutations. Using specialized feature selection models we identify descriptors that are highly specific and, conversely, broadly important to predicting the effects of different classes of mutations, interface regions and complexes. Our results also indicate that the distribution of the critical stability regions across protein-protein interfaces is a function of complex size more strongly than interface area. In addition, mutations at the rim are critical for the stability of small complexes, but consistently harder to characterize. The relationship between hotregion size and the dissociation rate is also investigated and, using hotspot descriptors which model cooperative effects within hotregions, we show how the contribution of hotregions of different sizes, changes under different cooperative effects.
authors.affiliation: Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, London, United Kingdom.
authors.forename: Rudi
authors.initials: R
authors.lastname: Agius
authors.forename: Mieczyslaw
authors.initials: M
authors.lastname: Torchala
authors.forename: Iain H
authors.initials: IH
authors.lastname: Moal
authors.forename: Juan
authors.initials: J
authors.lastname: Fernández-Recio
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bates
mesh_terms: D000409:Alanine / Q000737:chemistry; D001185:Artificial Intelligence; D007700:Kinetics; D009154:Mutation; D011506:Proteins / Q000737:chemistry* / Q000235:genetics
chemical_list: D011506:Proteins; D000409:Alanine
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):57-62
references.pmid: 15618400
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D829-33
references.pmid: 22080558
references.citation: Nucleic Acids Res. 2009 May;37(8):2672-87
references.pmid: 19273533
references.citation: Curr Pharm Des. 2012;18(30):4607-18
references.pmid: 22650255
references.citation: PLoS One. 2012;7(6):e39360
references.pmid: 22737235
references.citation: J Am Chem Soc. 2009 Feb 18;131(6):2074-5
references.pmid: 19170596
references.citation: Biochemistry. 1996 Sep 3;35(35):11435-46
references.pmid: 8784199
references.citation: J Mol Biol. 2010 Nov 5;403(4):660-70
references.pmid: 20868694
references.citation: Curr Opin Drug Discov Devel. 2009 Jul;12(4):488-96
references.pmid: 19562645
references.citation: Q Rev Biophys. 2010 May;43(2):219-93
references.pmid: 20691138
references.citation: PLoS Comput Biol. 2007 Jul;3(7):e119
references.pmid: 17630824
references.citation: Fold Des. 1996;1(6):R121-6
references.pmid: 9080186
references.citation: PLoS One. 2009 Dec 24;4(12):e8470
references.pmid: 20041122
references.citation: Chem Rev. 2009 Mar 11;109(3):839-60
references.pmid: 19196002
references.citation: PLoS Comput Biol. 2012;8(10):e1002738
references.pmid: 23093928
references.citation: Protein Sci. 1999 Jun;8(6):1181-90
references.pmid: 10386868
references.citation: Nucleic Acids Res. 2010 Jul;38(Web Server issue):W402-6
references.pmid: 20444871
references.citation: Curr Opin Struct Biol. 2007 Apr;17(2):166-72
references.pmid: 17395455
references.citation: FEBS Lett. 2009 Apr 2;583(7):1060-6
references.pmid: 19275897
references.citation: Proteins. 2011 Sep;79(9):2671-83
references.pmid: 21735484
references.citation: J Mol Biol. 1996 Mar 1;256(3):623-44
references.pmid: 8604144
references.citation: Brief Funct Genomics. 2012 Nov;11(6):543-60
references.pmid: 22811516
references.citation: Expert Opin Drug Discov. 2010 Apr;5(4):305-10
references.pmid: 22823083
references.citation: Integr Biol (Camb). 2011 Jul;3(7):724-32
references.pmid: 21674097
references.citation: Mol Biosyst. 2009 Apr;5(4):323-34
references.pmid: 19396368
references.citation: Bioinformatics. 2010 Mar 1;26(5):689-91
references.pmid: 20061306
references.citation: J Med Chem. 2002 Dec 5;45(25):5430-9
references.pmid: 12459011
references.citation: J Mol Biol. 1998 Apr 17;277(5):1111-28
references.pmid: 9571026
references.citation: J Mol Recognit. 1992 Sep;5(3):105-14
references.pmid: 1298302
references.citation: Methods Mol Biol. 2006;340:235-49
references.pmid: 16957340
references.citation: Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W382-8
references.pmid: 15980494
references.citation: Curr Top Med Chem. 2007;7(10):999-1005
references.pmid: 17508933
references.citation: J Mol Biol. 2005 Apr 1;347(3):489-94
references.pmid: 15755445
references.citation: J Biol Chem. 1996 Dec 27;271(52):33231-5
references.pmid: 8969180
references.citation: PLoS Comput Biol. 2012;8(8):e1002623
references.pmid: 22876170
references.citation: Bioinformatics. 2001 Mar;17(3):284-5
references.pmid: 11294795
references.citation: J Mol Biol. 2005 Feb 4;345(5):1281-94
references.pmid: 15644221
references.citation: BMC Bioinformatics. 2009 Oct 30;10:365
references.pmid: 19878545
references.citation: Hum Mutat. 2012 Feb;33(2):359-63
references.pmid: 22072597
references.citation: J Comput Chem. 2009 Jul 30;30(10):1545-614
references.pmid: 19444816
references.citation: Bioinformatics. 2011 Nov 1;27(21):3002-9
references.pmid: 21903632
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9223-8
references.pmid: 15197281
references.citation: Proc Natl Acad Sci U S A. 2008 May 6;105(18):6608-13
references.pmid: 18443295
references.citation: Protein Sci. 1994 Dec;3(12):2351-7
references.pmid: 7538848
references.citation: J Med Chem. 2007 Mar 22;50(6):1231-40
references.pmid: 17305325
references.citation: Nat Struct Biol. 2002 Dec;9(12):906-11
references.pmid: 12426582
references.citation: PLoS Comput Biol. 2012 Jan;8(1):e1002351
references.pmid: 22253587
references.citation: Protein Sci. 2011 Mar;20(3):482-91
references.pmid: 21213247
references.citation: Biophys J. 2001 Feb;80(2):635-42
references.pmid: 11159432
references.citation: BMC Struct Biol. 2010 Nov 15;10:40
references.pmid: 21078143
references.citation: J Mol Biol. 2011 Nov 11;413(5):1047-62
references.pmid: 21945116
references.citation: PLoS One. 2011 Apr 29;6(4):e19268
references.pmid: 21559397
references.citation: Proc Natl Acad Sci U S A. 1993 May 1;90(9):4246-50
references.pmid: 8483940
references.citation: Mol Biosyst. 2010 Dec;6(12):2351-62
references.pmid: 20725658
references.citation: Proteins. 2009 Apr;75(1):104-10
references.pmid: 18798570
references.citation: Science. 1989 Jun 2;244(4908):1081-5
references.pmid: 2471267
references.citation: Proteins. 2001 Nov 15;45(3):190-8
references.pmid: 11599022
references.citation: J Struct Biol. 2004 Apr-May;146(1-2):166-79
references.pmid: 15037248
references.citation: Sci Signal. 2009 Jul 28;2(81):ra38
references.pmid: 19638615
references.citation: Biochemistry. 1999 Oct 19;38(42):13960-7
references.pmid: 10529242
references.citation: BMC Bioinformatics. 2010 Apr 08;11:174
references.pmid: 20377884
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14116-21
references.pmid: 12381794
references.citation: PLoS One. 2011 Feb 28;6(2):e16774
references.pmid: 21386962
references.citation: J R Soc Interface. 2012 Dec 12;10(79):20120835
references.pmid: 23235262
references.citation: J Mol Biol. 1998 Jul 3;280(1):1-9
references.pmid: 9653027
references.citation: Proteins. 2011 Mar;79(3):720-34
references.pmid: 21287608
references.citation: Bioinformatics. 2003 Jul 22;19(11):1453-4
references.pmid: 12874065
references.citation: Protein Eng Des Sel. 2012 Mar;25(3):119-26
references.pmid: 22258275
references.citation: Curr Pharm Des. 2012;18(9):1255-65
references.pmid: 22316154
references.citation: Biopolymers. 2001 Nov;59(6):427-33
references.pmid: 11598877
references.citation: J Exp Med. 2007 Dec 24;204(13):3157-72
references.pmid: 18070938
references.citation: BMC Bioinformatics. 2007 May 24;8 Suppl 5:S8
references.pmid: 17570867
references.citation: Biophys J. 2008 Nov 1;95(9):4217-27
references.pmid: 18676649
references.citation: Trends Biochem Sci. 2010 Oct;35(10):539-46
references.pmid: 20541943
references.citation: J Mol Biol. 2000 May 5;298(3):503-20
references.pmid: 10772866
references.citation: Nucleic Acids Res. 2007;35(16):5275-83
references.pmid: 17617646
references.citation: Bioinformatics. 2012 Oct 15;28(20):2600-7
references.pmid: 22859501