A theoretical model is presented for the free energy ΔGb of complex formation between a highly charged polyelectrolyte and a protein. The model introduced here comprises both the effect of released counterions and the uptake or release of water molecules during complex formation. The resulting expression for ΔGb is hence capable of describing the dependence of ΔGb on temperature as well as on the concentration of salt in the system: An increase of the salt concentration in the solution increases the activity of the ions and counterion release becomes less effective for binding. On the other hand, an increased salt concentration leads to the decrease of the activity of water in bulk. Hence, release of water molecules during complex formation will be more advantageous and lead to an increase of the magnitude of ΔGb and the binding constant. It is furthermore demonstrated that the release or uptake of water molecules is the origin of the marked enthalpy–entropy cancellation observed during complex formation of polyelectrolytes with proteins. The comparison with experimental data on complex formation between a synthetic (sulfated dendritic polyglycerol) and natural polyelectrolytes (DNA; heparin) with proteins shows full agreement with theory.
Evidence is strengthening to suggest that the novel SARS-CoV-2 mutant Omicron, with its more than 60 mutations, will spread and dominate worldwide. Although the mutations in the spike protein are known, the molecular basis for why the additional mutations in the spike protein that have not previously occurred account for Omicron's higher infection potential, is not understood. We propose, based on chemical rational and molecular dynamics simulations, that the elevated occurrence of positively charged amino acids in certain domains of the spike protein (Delta: + 4; Omicron: + 5 vs. wild type) increases binding to cellular polyanionic receptors, such as heparan sulfate due to multivalent charge-charge interactions. This observation is a starting point for targeted drug development.
We study the thermodynamics of the interaction between human serum albumin (HSA) and dendritic polyglycerol sulfate (dPGS) of different sizes (generations) by isothermal titration calorimetry (ITC) and computer simulations. The analysis by ITC revealed the formation of a 1:1 complex for the dPGS-G2 of second generation. The secondary structure of HSA remained unchanged in the presence of dPGS-G2, as shown by circular dichroism. For higher generations, several HSA are bound to one polymer (dPGS-G4: 2; dPGS-G5.5: 4). The Gibbs free energy ΔGb was determined at different temperatures and salt concentrations. The binding constant Kb exhibited a logarithmic dependence on the salt concentration thus indicating a marked contribution of counterion-release entropy to ΔGb. The number of released counterions (∼4) was found to be independent of temperature. In addition, the temperature dependence of ΔGb was small, whereas the enthalpy ΔHITC was found to vary strongly with temperature. The corresponding heat capacity change ΔCp,ITC for different generations was of similar values [8 kJ/(mol K)]. The nonlinear van’t Hoff analysis of ΔGb revealed a significant heat capacity change ΔCp,vH of similar magnitude [6 kJ/(mol K)] accompanied by a strong enthalpy-entropy compensation. ΔGb obtained by molecular dynamics simulation with implicit water and explicit ions coincided with experimental results. The agreement indicates that the enthalpy-entropy compensation assigned to hydration effects is practically total and the binding affinity is fully governed by electrostatic interactions.
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