Migration of HSSH/HSS- Inside Myoglobin

CÓRDOVA, JONATHAN A; ESTRIN, DARÍO A.; BARI, SARA E.; PALERMO, JUAN CRUZ; CAPECE, LUCIANA

Congreso; 51ª Reunião Anual da Sociedade Brasileira de Bioquímica e Biologia Molecular (SBBq)/ 46o Congresso Brasileiro de Biofísica (SBBf/LAFEBS)); 2022

During the last decades, the study of reactive sulfur species (RSS) in biochemistryhas increased since the introduction of H2S as a signaling function. Due to theimportance of RSS, our research group contributed to the comprehension ofbiochemical mechanisms associated with the relevance of sulfur species. It has beendemonstrated that disulfane, HSSH, or its conjugated base HSS-, but not H2S, is thesignaling species in certain tissues.Hence, the first step to understanding the reactivity of sulfur species towards hemeproteins starts with the migration of the ligand from the bulk to the active site. In thiscontext, the present work studies the migration of HSSH and HSS- from the bulk tothe heme myoglobin active site. At this point, it is important to determine whichspecies are present in the bio-relevant environment; thus, the pKa of HSSH is alsocomputed, in order to estimate the population of each form.For that purpose, we applied a combination of computer simulation techniques,including steered classical molecular dynamics simulations and Jarzynski’sinequality to determine the free energy profile of migration of the ligand to the activesite, and QM calculations to estimate the HSSH pKa.Our results suggest that HSSH is more acidic than H2S. Migration free energyprofiles of HSSH/HSS- in myoglobin exhibit a similar behavior than the previouslyobserved for the H2S/HS-, and together with the acid-base equilibrium informationcompletes the picture of HSSH binding in myoglobin.Based on our results, it is possible to mention that the conjugate base of disulfane isthe most probable specie present in the bio-relevant environment, and HSSHmigrates to the active site of myoglobin in the same way as H2S does.