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Methods Mol Biol

Title:		Homology Modeling in the Twilight Zone: Improved Accuracy by Sequence Space Analysis
Author(s):		Ben Boubaker R; Tiss A; Henrion D; Chabbert M;
Address:		"UMR CNRS 6015 - INSERM 1083, Laboratoire MITOVASC, Universite d'Angers, Angers, France. UMR CNRS 6015 - INSERM 1083, Laboratoire MITOVASC, Universite d'Angers, Angers, France. marie.chabbert@univ-angers.fr"
Journal Title:		Methods Mol Biol
Year:		2023
Volume:		2627
Issue:
Page Number:		1 - 23
DOI:		10.1007/978-1-0716-2974-1_1
ISSN/ISBN:		1940-6029 (Electronic) 1064-3745 (Linking)
Abstract:		"The analysis of the relationship between sequence and structure similarities during the evolution of a protein family has revealed a limit of sequence divergence for which structural conservation can be confidently assumed and homology modeling is reliable. Below this limit, the twilight zone corresponds to sequence divergence for which homology modeling becomes increasingly difficult and requires specific methods. Either with conventional threading methods or with recent deep learning methods, such as AlphaFold, the challenge relies on the identification of a template that shares not only a common ancestor (homology) but also a conserved structure with the query. As both homology and structural conservation are transitive properties, mining of sequence databases followed by multidimensional scaling (MDS) of the query sequence space can reveal intermediary sequences to infer homology and structural conservation between the query and the template. Here, as a case study, we studied the plethodontid receptivity factor isoform 1 (PRF1) from Plethodon jordani, a member of a pheromone protein family present only in lungless salamanders and weakly related to cytokines of the IL6 family. A variety of conventional threading methods led to the cytokine CNTF as a template. Sequence mining, followed by phylogenetic and MDS analysis, provided missing links between PRF1 and CNTF and allowed reliable homology modeling. In addition, we compared automated models obtained from web servers to a customized model to show how modeling can be improved by expert information"
Keywords:		"Phylogeny *Ciliary Neurotrophic Factor *Software Sequence Analysis, Protein/methods Cytokines Algorithms Cytokine Molecular modeling Plethodontid receptivity factor Profile-profile mining Threading Twilight zone;"
Notes:		"MedlineBen Boubaker, Rym Tiss, Asma Henrion, Daniel Chabbert, Marie eng Research Support, Non-U.S. Gov't 2023/03/25 Methods Mol Biol. 2023; 2627:1-23. doi: 10.1007/978-1-0716-2974-1_1"