Fernández-Recio, Juan

Rosell, Mireia

UPCommons

Characteritzation of pathological mutations affecting protein-protein interactions for drug discovery

UPCommons. Portal del coneixement obert de la UPC

Characteritzation of pathological mutations affectingprotein-protein interactions for drug discoveryMireia Rosell∗, Juan Ferna´ndez-Recio∗†∗Barcelona Supercomputing Center, Barcelona, Spain†Institut de Biologia Molecular de Barcelona (IBMB), CSIC, Barcelona, SpainE-mail: {mireia.rosell, juan.fernandez}@bsc.esKeywords—Hot-spots, protein-protein docking, structural vari-ants, binding effect.I. EXTENDED ABSTRACTPathogenic single nucleotide variants (SNV) can affectbinding affinity or change the specificity of a protein-proteininteraction (PPI). It is a known fact that modulating PPIs withsmall molecules is a long sought strategy in drug discovery. Weface three major problems: i) the lack of available structuresfor the majority of PPIs in human; ii) the absence of naturalcavities in protein-protein interfaces that could be used to iden-tify small molecules as in standard enzyme inhibitor discovery;and iii) how a small molecule can compete with a large proteininterface. We have developed a strategy for identifying smallmolecule inhibitors of PPIs when complex structure is notavailable, based on the integration of molecular dynamics withAmber for the generation of transient cavities, FPocket for theidentification of such cavities [1], and computational dockingcalculations and hot-spot predictions with pyDock to select thebest cavities for PPI modulation[2,3].However, estimating the effects of a given single nucleotidevariant on a PPI is extremely challenging. We aim to apply thismethodology to known pathological variants from Humsavarand ClinVar databases that affect PPIs. There are very fewexperimental data for the effect on binding affinity of theseSNVs (according to SKEMPI database)[4,5]. Thus, in orderto estimate this effect, we initially mapped these structuralvariants on protein-protein complex structures included in theProtein-Protein Docking Benchmark 5 (formed by complexeswith available structure for the complex as well as for theunbound components)[6]. The effect of these SNV on bindingaffinity is predicted with mCSM[7], pyDock and FoldX[8].Then, for the protein-protein interactions that are stabilized bypathological variants, we will test on the unbound componentsof the Docking Benchmark the identification of cavities suit-able to find possible small molecule inhibitors.II. ACKNOWLEDGMENTSThis work has been funded by grants BIO2016-79930-Rand Severo Ochoa program SEV-2015-0493 from the SpanishMinistry of Economy, Industry and Competitiveness and bySevero Ochoa mobility grant.REFERENCES[1] Le Guilloux V, Schmidtke P, Tuffery P. Fpocket:an open source platform for ligand pocket detection. BMCBioinformatics. 2009;10:168.[2] Grosdidier S, Ferna´ndez-Recio J. Identification of hot-spot residues in protein-protein interactions by computationaldocking. BMC Bioinformatics. 2008;9:447.[3] Cheng TM, Blundell TL, Ferna´ndez-Recio J. pyDock:electrostatics and desolvation for effective scoring of rigid-body proteinprotein docking. Proteins. 2007;68:503515.[4] Moal IH, Ferna´ndez-Recio J. SKEMPI: a struc-tural kinetic and energetic database of mutant protein in-teractions and its use in empirical models. Bioinformatics.2012;28:26002607.[5] David A, Sternberg MJE. The contribution of missensemutations in core and rim residues of protein-protein interfacesto human disease. J Mol Biol. 2015;427:28862898.[6] Vreven, T., Moal, I. H., Vangone, A., Pierce, B. G.,Kastritis, P. L., Torchala, M., et al. Updates to the integratedproteinprotein interaction benchmarks: Docking benchmarkversion 5 and affinity benchmark version 2. Journal of Molec-ular Biology. 2015, 427(19), 30313041.[7] Pires DEV, Ascher DB, Blundell TL. mCSM: predictingthe effects of mutations in proteins using graph-based signa-tures. L.Bioinformatics. 2014,30(3):335-342.[8] Schymkowitz J, Borg J, Stricher F, Nys R, Rousseau F,Serrano L. The FoldX web server: an online force field. Nu-cleic Acids Research. 2005,33(Web Server issue): W382W388.Mireia Rosell is a PhD student at the ProteinInteractions and Docking Group in the BarcelonaSupercomputing Center, lead by Juan Ferna´ndez-Recio. She did a B.Sc. In Biochemistry at UniversitatAuto´noma de Barcelona and afterwards she obtainedan interuniversity M.Sc. in Bioinformatics for HealthSciences by Universitat Pompeu Fabra and Univer-sitat de Barcelona. Her research is focused on thedevelopment of a new methodology for the high-throughput structural annotation of sequence variantsinvolved in protein interactions.5th BSC Severo Ochoa Doctoral Symposium56

https://upcommons.upc.edu/bitstream/2117/124972/1/23-CHARACTERITZATION%20OF%20PATHOLOGICAL.pdf

Characteritzation of pathological mutations affecting protein-protein interactions for drug discovery

Abstract

Similar works

Full text

Available Versions

UPCommons

UPCommons. Portal del coneixement obert de la UPC