Understanding Conformational Properties and Role of Hydrogen Bonds in Glycosaminoglycans‐Interleukin8 Complexes in Aqueous Medium by Molecular Dynamics Simulation

Abstract

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.

Sulfation Effects of Chondroitin Sulfate to Bind a Chemokine in Aqueous Medium: Conformational Heterogeneity and Dynamics from Molecular Simulation

“…39 Recently, we showed that the recognition of protein and hexameric CS occurred through water-mediated H-bonds. 35 We adopted the Luzar−Chandler model to study the kinetics of different trapped H-bonds associated with the binding process.…”

“…In another study on CS disaccharide torsional space, intra- and intermolecular H-bonds, bridging water molecules, and principal component analysis suggest that the distinct conformational dynamics in different CS disaccharides is the reason for the existence of unique electrostatic surfaces that could be a key for protein recognition . Recently, we showed that the recognition of protein and hexameric CS occurred through water-mediated H-bonds . We adopted the Luzar–Chandler model to study the kinetics of different trapped H-bonds associated with the binding process.…”

“…Raman optical activity (ROA) spectra are sensitive to both sugar ring puckering and a longer-range order of the glycosidic chain . Computational studies in general and molecular simulations in practical have been successful in exploring complex conformational features of different free GAGs or their monosaccharide/repeating disaccharide units ,− and GAG–protein interactions. , A previous study on MD simulation of CS tetrasaccharide characterized the hydration properties and H-bonding phenomenon . The study showed that compared to non-sulfated oligosaccharides, CS is highly hydrated; interestingly, the hydration also remains high when they bind to proteins .…”