In Silico Study of a Cystein Precursor: N-Acetylcysteine

HUGO A. PÉREZ; MARCELO ARIAS

Córdoba

Congreso; LI Reunión Anual de la Sociedad Argentina de Biofísica; 2023

Sociedad Argentina de Biofísica

Since several years, N-acetylcysteine (NAC) hasbeen used as a mucolytic agent and for the treatment of numerous disorders,including acetaminophen intoxication, doxorubicin cardiotoxicity,ischemia-reperfusion cardiac injury, and acute respiratory distress syndrome.NAC is a derivative of cysteine with an acetyl group attached to its nitrogenatom. Like most thiols (RSH), NAC can be oxidized by a large variety ofradicals and serve as a nucleophile (electron pair donor). All the processes described above must firstcross the cell membrane of the different epithelia. Therefore, it is of vitalinterest to understand the phenomena that occur at the membrane level. In thisregard, we used molecular dynamics, the interaction of Cysteine (Cys) and NAC with modelmembranes at different physiological pH to understand the phenomena that occur.Onthis occasion, umbrella sampling was carried out at pH 7 and 2 corresponding tothe cell and digestive pH, respectively. Umbrella sampling was used tocalculate free energy profiles for the partitioning of molecules in the lipidbilayer. PMFs show large free energy gradients as amino acids move across themembrane, with different behavior depending on the charge of amino acid. OurPMFs calculations for pH 2, show global minima in the free energy curves at -24Kcal mol-1 for Cys and -8.5 Kcal mol-1 for NAC atapproximate distances of 1.4 nm from the center of the bilayer, for both cases.The minima for both PMFs are centered in the region where the glycerol chainand carbonyl groups meet in the lipid bilayer (Region II). For pH 7, thesevalues give -19.6 Kcal mol-1 for Cys and -11.3 Kcal mol-1for NAC, placing these global minima in the same region as at pH 2, the minimafor both PMFs are near the center of Region II, consistent with the slightlyamphipathic nature of these molecule. This location is congruent with previousexperimental determinations, where a dehydration effect of the bilayer causedby the presence of NAC and Cys could be observed