title: Theoretical structural characterization of lymphoguanylin: A potential candidate for the development of drugs to treat gastrointestinal disorders.
abstract: Guanylin peptides (GPs) are small cysteine-rich peptide hormones involved in salt absorption, regulation of fluids and electrolyte homeostasis. This family presents four members: guanylin (GN), uroguanylin (UGN), lymphoguanylin (LGN) and renoguanylin (RGN). GPs have been used as templates for the development of drugs for the treatment of gastrointestinal disorders. Currently, LGN is the only GP with only one disulfide bridge, making it a remarkable member of this family and a potential drug template; however, there is no structural information about this peptide. In fact, LGN is predicted to be highly disordered and flexible, making it difficult to obtain structural information using in vitro methods. Therefore, this study applied a series of 1μs molecular dynamics simulations in order to understand the structural behavior of LGN, comparing it to the C115Y variant of GN, which shows the same Cys to Tyr modification. LGN showed to be more flexible than GN C115Y. While the negatively charged N-terminal, despite its repellent behavior, seems to be involved mainly in pH-dependent activity, the hydrophobic core showed to be the determinant factor in LGN's flexibility, which could be essential in its activity. These findings may be determinant in the development of new medicines to help in the treatment of gastrointestinal disorders. Moreover, our investigation of LGN structure clarified some issues in the structure-activity relationship of this peptide, providing new knowledge of guanylin peptides and clarifying the differences between GN C115Y and LGN.
authors.affiliation: Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília-DF, Brazil; Centro de Análises Proteômicas e Bioquímicas, Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília-DF, Brazil.
authors.forename: Állan S
authors.initials: ÁS
authors.lastname: Pires
authors.affiliation: Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília-DF, Brazil; Centro de Análises Proteômicas e Bioquímicas, Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília-DF, Brazil; Porto Reports, Brasília-DF, Brazil.
authors.forename: William F
authors.initials: WF
authors.lastname: Porto
authors.affiliation: Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília-DF, Brazil.
authors.forename: Pryscilla O
authors.initials: PO
authors.lastname: Castro
authors.affiliation: Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília-DF, Brazil; Centro de Análises Proteômicas e Bioquímicas, Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília-DF, Brazil; S-Inova Biotech, Pós-graduação em Biotecnologia, Universidade Católica Dom Bosco,, Campo Grande, MS, Brazil.
authors.forename: Octavio L
authors.initials: OL
authors.lastname: Franco
authors.affiliation: Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília-DF, Brazil. Electronic address: sergiodealencar@gmail.com.
authors.forename: Sérgio A
authors.initials: SA
authors.lastname: Alencar
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003198:Computer Simulation; D005767:Gastrointestinal Diseases / Q000188:drug therapy*; D005768:Gastrointestinal Hormones / Q000737:chemistry / Q000235:genetics; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D020125:Mutation, Missense; D045265:Natriuretic Peptides / Q000737:chemistry / Q000235:genetics; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity; D013329:Structure-Activity Relationship
chemical_list: D005768:Gastrointestinal Hormones; D045265:Natriuretic Peptides; D010455:Peptides; C118275:lymphoguanylin; C072685:guanylin
keywords: Core flexibility; Disordered protein; Guanylin peptides; Molecular dynamics