Interactions of the male contraceptive target EPPIN with semenogelin-1 and small organic ligands.

Novel male contraceptives will promote gender equality in sharing contraceptive responsibility. The sperm-associated protein epididymal protease inhibitor (EPPIN) is a promising target for non-hormonal male contraception. EPPIN interacts with the semen coagulum protein semenogelin-1 (SEMG1) on the sperm surface, leading to transient inhibition of sperm motility after ejaculation. Small organic molecules targeting EPPIN's SEMG1-binding are under development as male contraceptives. Here, we combined computational approaches to uncover key aspects underlying EPPIN binding to SEMG1 and small organic ligands. We generated a human EPPIN model showing a typical arrangement of the WFDC (Whey-acid four disulfide core)-type and Kunitz-type domains, connected by a hinge region. Determining the EPPIN model's intrinsic motion by molecular dynamics simulations and normal mode analysis revealed a conformation, presenting a binding pocket that accommodates SEMG1Glu229-Gln247, EP055, and EP012. EPPIN's residues Phe63 and Lys68 (WFDC domain), Asp71 (hinge region), and Asn113, Asn114, and Asn115 (Kunitz domain) were identified as hot spots for SEMG1, EP055, and EP012 binding. Moreover, hydrophobic and hydrophilic residues in the WFDC and Kunitz domains allow plasma membrane anchoring, orienting the EPPIN binding pocket to the solvent. Targeting EPPIN's essential residues for its biomolecular interactions may improve the rational design of EPPIN ligands as spermiostatic compounds.

Sensitivity is the dimension of temperament most associated with the progression from ideation to suicide attempts.

BACKGROUND: To analyze the association between temperament (emotional and affective) and scrutinize the progression from suicide ideation to attempt, by using data from a large internet-based sample. METHODS: It is a cross-sectional study, based on the Brazilian Internet Study on Temperament and Psychopathology (BRAINSTEP). Temperament was assessed by the Affective and Emotional Composite Temperament Scale (AFECTS), and life-long suicidal behavior was determined by the adapted Suicidal Behaviors Questionnaire (SBQ-17). Odds ratios were obtained through multivariate logistic regression and a multiple linear regression were used in the analysis. According to the "ideation-to-action framework", we performed analyzes using two different reference groups: no suicidal ideation and suicidal ideation. RESULTS: The affective temperaments that showed the greatest association with suicide attempts were depressive, cyclothymic, and volatile. The temperaments that reflected higher associations for progression from ideation to suicide attempt were cyclothymic, depressive, and euphoric. Sensitivity was manifested as the emotional temperament with the strongest positive association with the severity of suicidal behavior, followed by desire and control. Stability was estimated as the emotional trait with the strongest negative association with the severity of suicidal behavior. LIMITATIONS: It is not a population based sample. BRAINSTEP is a self-selected sample whose participants are mostly women, who are highly educated and young. CONCLUSIONS: Our results suggest that temperament assessment using AFECT model may be relevant to assess the risk for the progression from ideation to suicide attempts. These results strengthen the "ideation-to-action" framework that risk factors to suicide ideators can differ from suicide attempters.