Role of surface-exposed charged basic amino acids (Lys, Arg) and guanidination in insulin on the interaction and stability of insulin–insulin receptor complex

Autor: Umah Rani Kuppusamy, Pak Kheong Tan, Vannajan Sanghiran Lee, Sri Devi Sukumaran, Bavani Arumugam
Rok vydání: 2021
Předmět:
Zdroj: Computational Biology and Chemistry. 92:107501
ISSN: 1476-9271
DOI: 10.1016/j.compbiolchem.2021.107501
Popis: Naturally occurring proteins are emerging as novel therapeutics in the protein-based biopharmaceutical industry for the treatment of diabetes and obesity. However, proteins are not suitable for oral delivery due to short half-life, reduced physical and chemical stability and low permeability across the membrane. Chemical modification has been identified as a formulation strategy to enhance the stability and bioavailability of protein drugs. The present study aims to study the effect of charge-specific modification of basic amino acids (Lys, Arg) and guanidination on the interaction of insulin with its receptor using molecular modelling. Our investigation revealed that the guanidination of insulin (Lys-NHC = NHNH2) enhanced and exerted stronger binding of the protein to its receptor through electrostatic interaction than native insulin (Lys-NH3+). Point mutations of Lys and Arg (R22, K29; R22K, K29; R22, K29R; R22K, K29R) were attempted and the effects on the interaction and stability between insulin/modified insulins and insulin receptor were also analyzed in this study. The findings from the study are expected to provide a better understanding of the possible mechanism of action of the modified protein at a molecular level before advancing to real experiments.
Databáze: OpenAIRE
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