title: Molecular modeling in the age of clinical genomics, the enterprise of the next generation.
abstract: Protein modeling and molecular dynamics hold a unique toolset to aide in the characterization of clinical variants that may result in disease. Not only do these techniques offer the ability to study under characterized proteins, but they do this with the speed that is needed for time-sensitive clinical cases. In this paper we retrospectively study a clinical variant in the XIAP protein, C203Y, while addressing additional variants seen in patients with similar gastrointestinal phenotypes as the C203Y mutation. In agreement with the clinical tests performed on the C203Y patient, protein modeling and molecular dynamics suggest that direct interactions with RIPK2 and Caspase3 are altered by the C203Y mutation and subsequent loss of Zn coordination in the second BIR domain of XIAP. Interestingly, the variant does not appear to alter interactions with SMAC, resulting in further damage to the caspase and NOD2 pathways. To expand the computational strategy designed when studying XIAP, we have applied the molecular modeling tools to a list of 140 variants seen in CFTR associated with cystic fibrosis, and a list of undiagnosed variants in 17 different genes. This paper shows the exciting applications of molecular modeling in the classification and characterization of genetic variants identified in next generation sequencing. Graphical abstract XIAP in Caspase 3 and NOD2 signaling pathways.
authors.affiliation: HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, 35806, USA. jprokop54@gmail.com.|Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. jprokop54@gmail.com.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Prokop
authors.affiliation: HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, 35806, USA.|Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
authors.forename: Jozef
authors.initials: J
authors.lastname: Lazar
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Crapitto
authors.affiliation: HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, 35806, USA.
authors.forename: D Casey
authors.initials: DC
authors.lastname: Smith
authors.affiliation: HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, 35806, USA.|Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Worthey
authors.affiliation: HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, 35806, USA.|Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Jacob
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology; D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3 / Q000737:chemistry / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000235:genetics; D015894:Genome, Human; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000737:chemistry* / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000737:chemistry* / Q000235:genetics
chemical_list: C505032:CFTR protein, human; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D051636:X-Linked Inhibitor of Apoptosis Protein; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D053148:Caspase 3
keywords: Caspase3; Clinical variants; Protein modeling; RIPK2; SMAC; Undiagnosed and rare diseases; XIAP