Suggested possible site of Fusexin-1 modulation

DIEGO OBIOL; FERNANDO ZAMARREÑO; AGUSTÍN VIETRI; SILVIA ANTOLLINI; MARCELO D. COSTABEL

Rosario

Congreso; L Reunión Anual de la Sociedad Argentina de Biofísica; 2022

Sociedad Argentina de Biofísica

Recently it was determined that sexual reproduction evolved from fusexins, a family ofproteins known as fusogens and identified in archaeobacteria. Intrigued by the fact thatthis family of proteins could be responsible for sexual reproduction of plants, protozoa andinvertebrates, and considering that viral fusion proteins belong to this family of proteins,we decided to investigate if there is a site that could be modulated and to identify somecharacteristics of a possible ligand. We used different softwares to determine potentialsites of action and molecules that have affinity to similar sites in Fusexin1 (Fsx1) (pdb:7P4L). We selected the pocket formed peripherally by domain II and domain III of chain A,at amino acids Val-306 and Thr-367, respectively; and inside the pocket, by domain I ofchain B and domain I of chain A, at AA Asp-172 and Ala-221, respectively. The ligand withthe best binding affinity score was 4-cyclohexylbutyl 4-O-Alpha-D-glucopyranosyl-Beta-Dglucopyranoside (CYMAL-4) which establishes hydrogen bonds with Ser-222, Asp-300,Val-396 and Asp-397 of chain A and with Ser-90 of chain B, all of which are less than 3Åof distance. We propose to design a battery of analogues of CYMAL-4 and performmolecular docking studies on them. Based on the binding affinity score, we propose to i)select the most relevant analogue(s) to perform molecular dynamics on them, taking as astarting point the best scored docking positions, ii) determine the dynamics` mostrepresentative ligand conformation as well as the type of bond it establishes with theamino acids of the site, and iii) develop molecular dynamics with ethanol as solvent todetermine hot spots of the proposed site.