Amino acids having basic side chains, as additives, are known to increase the stability of native-folded state of proteins, but their relative efficiency and the molecular mechanism are still controversial and obscure as well. In the present work, extensive atomistic molecular dynamics simulations were performed to investigate the hydration properties of aqueous solutions of concentrated arginine, histidine, and lysine and their comparative efficiency on regulating the conformational stability of the insulin monomer. We identified that in the aqueous solutions of the free amino acids, the nonuniform relaxation of amino acid–water hydrogen bonds was due to the entrapment of water molecules within the amino acid clusters formed in solutions. Insulin, when tested with these solutions, was found to show rigid conformations, relative to that in pure water. We observed that while the salt bridges formed by the lysine as an additive contributed more toward the direct interactions with insulin, the cation–π was more prominent for the insulin–arginine interactions. Importantly, it was observed that the preferentially more excluded arginine, compared to histidine and lysine from the insulin surface, enriches the hydration layer of the protein. Our study reveals that the loss of configurational entropy of insulin in arginine solution, as compared to that in pure water, is more as compared to the entropy loss in the other two amino acid solutions, which, moreover, was found to be due to the presence of motionally bound less entropic hydration water of insulin in arginine solution than in histidine or lysine solution.

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Atomistic molecular dynamics simulations were performed under ambient conditions to explore the conformational features and binding affinities of hexameric glycosaminoglycans (GAGs) with chemokine Interleukin8 (IL8) in an aqueous medium. We tried to understand the role of hydrogen bonds (HBs) involving conserved water in mediating the interactions. The Luzar‐Chandler model was adopted to study the kinetics of HB breaking and formation concerning different water‐mediated HBs. The conformational flexibilities of bound GAGs are due to the flexible glycosidic linkages than the occasional/rare ring pucker conformation. The free energy landscape constructed with ϕ, and ψ, depicted that different conformational minima associated with the glycosidic linkage flexibility of the GAGs in bound states are separated by energy barriers. The binding affinities of IL8 towards GAGs are favored through the electrostatic and non‐polar solvation interactions. 4‐different types of conserved water were explored in the solvent‐mediated binding of GAGs with IL8. The average lifetime of the IL8‐GAG direct HB pairs was ∼ten times less than the IL8‐GAG‐shared water HBs. This is due to the rapid establishment of HB breaking and reformation kinetics involving water of a shared layer. We find that despite the highly negatively charged surface of GAGs, the IL8 surface populated by non‐cationic amino acids could serve as a promising binding site in addition to the cationic surface of the protein.

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