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Albumin-Hyaluronan Interactions: Influence of Ionic Composition Probed by Molecular Dynamics.

ABSTRACT: The lubrication mechanism in synovial fluid and joints is not yet fully understood. Nevertheless, intermolecular interactions between various neutral and ionic species including large macromolecular systems and simple inorganic ions are the key to understanding the excellent lubrication performance. An important tool for characterizing the intermolecular forces and their structural consequences is molecular dynamics. Albumin is one of the major components in synovial fluid. Its electrostatic properties, including the ability to form molecular complexes, are closely related to pH, solvation, and the presence of ions. In the context of synovial fluid, it is relevant to describe the possible interactions between albumin and hyaluronate, taking into account solution composition effects. In this study, the influence of Na⁺, Mg²⁺, and Ca²⁺ ions on human serum albumin-hyaluronan interactions were examined using molecular dynamics tools. It was established that the presence of divalent cations, and especially Ca²⁺, contributes mostly to the increase of the affinity between hyaluronan and albumin, which is associated with charge compensation in negatively charged hyaluronan and albumin. Furthermore, the most probable binding sites were structurally and energetically characterized. The indicated moieties exhibit a locally positive charge which enables hyaluronate binding (direct and water mediated).

SUBMITTER: Beldowski P

PROVIDER: S-EPMC8625520 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Molecular association of proteins with nucleic acids is required for many biological processes essential to life. Electrostatic interactions via ion pairs (salt bridges) of nucleic acid phosphates and protein side chains are crucial for proteins to bind to DNA or RNA. Counterions around the macromolecules are also key constituents for the thermodynamics of protein-nucleic acid association. Until recently, there had been only a limited amount of experiment-based information about how ions and ionic moieties behave in biological macromolecular processes. In the past decade, there has been significant progress in quantitative experimental research on ionic interactions with nucleic acids and their complexes with proteins. The highly negatively charged surfaces of DNA and RNA electrostatically attract and condense cations, creating a zone called the ion atmosphere. Recent experimental studies were able to examine and validate theoretical models on ions and their mobility and interactions with macromolecules. The ionic interactions are highly dynamic. The counterions rapidly diffuse within the ion atmosphere. Some of the ions are released from the ion atmosphere when proteins bind to nucleic acids, balancing the charge via intermolecular ion pairs of positively charged side chains and negatively charged backbone phosphates. Previously, the release of counterions had been implicated indirectly by the salt-concentration dependence of the association constant.Recently, direct detection of counterion release by NMR spectroscopy has become possible and enabled more accurate and quantitative analysis of the counterion release and its entropic impact on the thermodynamics of protein-nucleic acid association. Recent studies also revealed the dynamic nature of ion pairs of protein side chains and nucleic acid phosphates. These ion pairs undergo transitions between two major states. In one of the major states, the cation and the anion are in direct contact and form hydrogen bonds. In the other major state, the cation and the anion are separated by water. Transitions between these states rapidly occur on a picosecond to nanosecond time scale. When proteins interact with nucleic acids, interfacial arginine (Arg) and lysine (Lys) side chains exhibit considerably different behaviors. Arg side chains show a higher propensity to form rigid contacts with nucleotide bases, whereas Lys side chains tend to be more mobile at the molecular interfaces. The dynamic ionic interactions may facilitate adaptive molecular recognition and play both thermodynamic and kinetic roles in protein-nucleic acid interactions.

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Albumin-Hyaluronan Interactions: Influence of Ionic Composition Probed by Molecular Dynamics.

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