Protein Specificity of Charged Sequences in Polyanions and Heparins

Abstract

Long-range electrostatic interactions are generally assigned a subordinate role in the high-affinity binding of proteins by glycosaminoglycans, the most highly charged biopolyelectrolytes. The discovery of high and low sulfation domains in heparan sulfates, however, suggests selectivity via complementarity of their linear sulfation patterns with protein charge patterns. We examined how charge sequences in anionic/nonionic copolymers affect their binding to a protein with prominent charge anisotropy. Experiments and united-atom Monte Carlo simulations, together with Delphi electrostatic modeling for the protein, confirm strongest binding when polyanion sequences allow for optimization of repulsive and attractive electrostatics. Simulations also importantly identified retention of considerable polyion conformational freedom, even for strong binding. The selective affinity for heparins of high and low charge density found for this protein is consistent with nonspecific binding to distinctly different protein charge domains. These findings suggest a more nuanced view of specificity than previously proposed for heparinoid-binding proteins.

Counterion condensation in short cationic peptides: Limiting mobilities beyond the Onsager–Fuoss theory

“…For the nonapeptides, the second term in Eq. (6), which contains the effect of the model electrolyte, including condensed counterions, accounts for as much as about 90% of the magnitude of the estimated limiting mobility in some cases. For the amino acids, the effect is much smaller in all cases and roughly consistent with OF theory.…”

Nanoengineering of Stimuli‐Responsive Protein‐Based Biomimetic Protocells as Versatile Drug Delivery Tools

“…Moreover, the approach developed can be generally extended for preparation of nanoparticles and nanospheres from various functioning components that are able to in principle form solute‐enriched droplets through liquid/liquid phase separation 31. 32 Overall, the facile, flexible, and generally suited nature of the approach, in association with tunable size, versatile encapsulation of guest molecules, and stimuli‐responsiveness, as well as post‐functionalization of colloidal sphere surfaces, provides new alternative opportunities for the design and development of protein‐based delivery vehicles towards a range of therapeutic and diagnostic applications.…”

“…Alternatively, spontaneous assembly of binary components such as proteins (e.g., albumin) and oppositely charged biopolymers by electrostatic attraction has been investigated and has recently attracted increasing attention 30–32. It is well known that strong electrostatic interactions between oppositely charged biopolymers classically result in formation of solute‐enriched droplets due to liquid/liquid phase separation.…”

Electrostatic Forces as Dominant Interactions Between Proteins and Polyanions: an ESI MS Study of Fibroblast Growth Factor Binding to Heparin Oligomers

“…There is growing evidence that strong binding occurs between globally negative proteins and polyanions when polyanion charge distributions are arranged in a way that minimizes long-range repulsion while optimizing short range attractions with locally positive protein domains [19]. This can result in a form of selectivity that does not arise from short-range interactions such as hydrogen-bonding or salt bridge formation [20–22]. Supporting this perspective, several groups suggested non-specific contributions to GAG interactions with growth factors.…”