Effect of Ion and Binding Site on the Conformation of Chosen Glycosaminoglycans at the Albumin Surface

Abstract

Albumin is one of the major components of synovial fluid. Due to its negative surface charge, it plays an essential role in many physiological processes, including the ability to form molecular complexes. In addition, glycosaminoglycans such as hyaluronic acid and chondroitin sulfate are crucial components of synovial fluid involved in the boundary lubrication regime. This study presents the influence of Na+, Mg2+ and Ca2+ ions on human serum albumin-hyaluronan/chondroitin-6-sulfate interactions examined using molecular docking followed by molecular dynamics simulations. We analyze chosen glycosaminoglycans binding by employing a conformational entropy approach. In addition, several protein-polymer complexes have been studied to check how the binding site and presence of ions influence affinity. The presence of divalent cations contributes to the decrease of conformational entropy near carboxyl and sulfate groups. This observation can indicate the higher affinity between glycosaminoglycans and albumin. Moreover, domains IIIA and IIIB of albumin have the highest affinity as those are two domains that show a positive net charge that allows for binding with negatively charged glycosaminoglycans. Finally, in discussion, we suggest some research path to find particular features that would carry information about the dynamics of the particular type of polymers or ions.

Keywords: conformational entropy; dihedral angles; frequency distribution; human serum albumin; hyaluronan.

Figure 1

Structure of (a) HSA-HA, (b) HSA-CS6 complexes for highest affinity result in CaCl${}_2$ solution (solution is transparent on the picture). HSA is depicted as ribbon (bottom parts of picture), and its domains are colored as follows: IA-pink, IB-violet, IIA-light green, IIB-green, IIIA-light blue, and IIIB-blue. HA and CS6 are depicted as ball-stick (top parts of picture). Light blue atoms represent carbon, dark blue nitrogen, red oxygen, green sulfur and white hydrogen. Snapshots was taken using YASARA software after 100 ns MD simulations [19].

Figure 2

Structures of (a) HA and (b) CS6 with dihedral angles: ${\mathrm{\Phi }}_{1-4}$—red circles, ${\mathrm{\Psi }}_{1-4}$—blue circles (N-G linkage), ${\mathrm{\Phi }}_{1-3}$—green circles, ${\mathrm{\Psi }}_{1-3}$—violet circles (G-N linkage).

Figure 3

Normalized histograms of values of angles (${\mathrm{\Phi }}_{1-4}$, ${\mathrm{\Psi }}_{1-4}$) (top) and (${\mathrm{\Phi }}_{1-3}$,${\mathrm{\Psi }}_{1-3}$) (bottom) for main chain CS6 with (a) Na${}^{+}$, (b) Ca${}^{2+}$, and (c) Mg${}^{2+}$. Angles were taken from the whole time series of the YASARA simulation. The symbol n is a number of angles’ pairs and is equal to number of angles type (24 for angles $1,4$ and 23 for angles $1,3$, cf. Section 2.1) multiplied by number of time points ($1,000$).

Figure 4

Normalized histograms of values of angles (${\mathrm{\Phi }}_{1-4}$, ${\mathrm{\Psi }}_{1-4}$) (top) and (${\mathrm{\Phi }}_{1-3}$,${\mathrm{\Psi }}_{1-3}$) (bottom) for main chain HA with (a) Na${}^{+}$, (b) Ca${}^{2+}$, and (c) Mg${}^{2+}$. Angles were taken from the whole time series of the YASARA simulation. The symbol n is a number of angles’ pairs and is equal to number of angles type (24 for angles $1,4$ and 23 for angles $1,3$, cf. Section 2.1) multiplied by number of time points ($1,000$).

Figure 5

Median, maximal and minimal entropy (over $N=10$ realizations) for chosen ions and angles pairs for CS6 (left panel) and HA (right panel). As we have $N=10$ realizations, the minimal entropy can by considered as the estimate of the 10’th percentile (first quantile), and the maximal one as the estimate of the 90’th percentile (9’th quantile).

Figure 6

Conformational entropy for CS6 with (a) Na${}^{+}$, (b) Ca${}^{2+}$, and (c) Mg${}^{2+}$, and HA with (d) Na${}^{+}$, (e) Ca${}^{2+}$ and (f) Mg${}^{2+}$.