Evaluation of pH change effects on the HSA folding and its drug binding characteristics, a computational biology investigation

• Published in: Proteins, structure, function, and bioinformatics Vol. 90; no. 11; pp. 1908 - 1925
• Main Authors: Gomari, Mohammad Mahmoudi, Rostami, Neda, Faradonbeh, Davood Rabiei, Asemaneh, Hamid Reza, Esmailnia, Giti, Arab, Shahriar, Farsimadan, Marziye, Hosseini, Arshad, Dokholyan, Nikolay V.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.11.2022; Wiley Subscription Services, Inc
• Subjects: Binding sites; computational biology; Computer applications; Diabetes mellitus; Distribution functions; Drug development; drug metabolism; Free energy; Human serum albumin; Molecular dynamics; pH effects; Pharmaceutical industry; Principal components analysis; Probability distribution; Probability distribution functions; protein folding; Protein structure; Renal failure; Secondary structure; Serum albumin; Structural analysis; Tertiary structure; Drug metabolism; pH; Human serum albumin; Protein folding; Computational biology
• ISSN: 0887-3585; 1097-0134; 1097-0134
• DOI: 10.1002/prot.26386

The binding of therapeutics to human serum albumin (HSA), which is an abundant protein in plasma poses a major challenge in drug discovery. Although HSA has several binding pockets, the binding site I on D2 and binding site II on D3 are the main binding pockets of HSA. To date, a few experiments have been conducted to examine the effects of the potential of hydrogen (pH) changes on HSA attributes. In the present investigation, the effect of acidic (pH 7.1) and basic states (pH 7.7) on HSA structure and its drug binding potency were examined in comparison with the physiological state (pH 7.4). For this purpose, molecular dynamics (MD), free energy landscape (FEL), principal component analysis (PCA), probability distribution function (PDF), tunnel‐cavity investigation, secondary structure analysis, docking study, and free energy investigation were employed to investigate the effect of pH changes on the structural characteristics of HSA at the atomic level. The results obtained from this study revealed the significant effect of pH alterations on the secondary and tertiary structure of HSA. In addition, HSA stability and its drug binding ability can be severely affected following pH changes. Given that pH change frequently occurs in various diseases such as cancer, diabetes, and kidney failure, therefore, pharmaceutical companies should allocate specific consideration to this subject throughout their drug design experiments.