Individual Sub-Domain Molecular Dynamics Analysis of Human Serum Albumin

Abstract

Human serum albumin (HSA) is a multidomain macromolecule with about 60% of the plasma protein made up of HSA. HSA is the most prevalent protein in the cardiovascular system and is responsible for the transportation of hydrophobic substrate molecules in human plasma and extravascular fluids. Due to its numerous binding opportunities, HSA is also a significant factor in blood oncotic pressure. HSA consists of the following sub-domains 1A, 1B, 2A, 2B, 3A, and 3B and whether a conformational shift has been caused or not, the function of HSA stays constant. The majority of the human plasma antioxidant capacity is accounted for by HSA, which also serves as a transporter for exogenous substances. Studying the molecular dynamics of each sub-domain of HSA will help better understand and design drugs in complex with HSA without changing the standard physicochemical properties of HSA. The 3D molecular structure of HSA was collected from the Research Collaboratory for Structural Bioinformatics PDB with a PDB code of 1AO6. Molecular dynamics simulations were conducted using GROMACS, with each time step equal to 2fs for a period of 10 ns. The prepared molecule was solvated in NaCl and water to resemble the physiological properties of blood. The energy minimization was performed for 50,000 steps; the energy was minimized for a pressure of 1 bar, a density of 1010 kg/m3, and a temperature of 300 kelvins. Equilibration of the molecule was conducted for 100 ps, and the production run was performed for 50,00,000 steps (10 ns). Analyzing the output of molecular dynamics studies will help in plotting the graphical representation of values of root mean square fluctuation (RMSF), root mean square deviation (RMSD), radius of gyration (RoG), and solvent accessible surface area (SASA). RMSD plots of all individual domains (1A, 1B, 2A, 2B, 3A, and 3B) show no significant fluctuations. The lower the fluctuations, the higher the stability of the molecule; sub-domain 2B was more stable, and sub-domain 3B was least stable when compared between the individual subdomains. RMSF plots show the peak value below 2 angstroms representing less mobility. RoG plots have shown no significant difference in changes during the time course of molecular dynamics simulations. While sub-domain 2B has the least RoG values, sub-domain 3B has the highest RoG values compared to the individual subdomains. HSA sub-domain 1A has a higher solvent-accessible surface area than the remaining domains. Overall, sub-domain 2B was highly stable RMSD, lesser RMSF, and less RoG, making it a perfect selection site for preparing drug complex and tissue protein complex with HSA without changing the structural confirmations of the HSA after complex formation and retaining its physicochemical properties.