Mannobiose‐Grafting Shifts PEI Charge and Biphasic Dependence on pH

Abstract

How the 4% grafting of mannobiose alters the properties of the polyelectrolyte, linear polyethylenimine (PEI), which has protonable amines and is used widely for complexing DNA, is investigated. The pH‐dependence of the PEI charge, zeta potential, and hydrodynamic radius changes when the polymer charge increases beyond 50–60%. According to MD simulations, this transition in pH‐ or charge‐ dependence is a short‐range structural response to amine protonation (i.e., change in intrinsic persistence length) rather than a longer‐range charge‐repulsion response. Upon mannobiosylation, the 50% charge state of PEI shifts from ≈pH 6 toward ≈pH 4. The protonability of PEI is lowered and restricted to limited charge states. These mannobiosylation‐induced shifts are reversed by salt and uncharged chaotropes, indicating that hydrogen‐bonding interactions fostered by the grafted sugars are lowering the protonation pKa of PEI. These findings have broad implications for the analytical modeling of polyelectrolytes, the design of PEI‐based gene‐delivery systems, and for understanding how oligosaccharides modify cell and protein surfaces.

Effect of the Protonation Level and Ionic Strength on the Structure of Linear Polyethyleneimine

“…Thus, the increased stiffness in this regime is likely related to the N–C–C–N torsional angle increasingly being in the trans configuration. Basu et al recently determined the persistence length of PEI at several protonation states using atomistic molecular dynamics simulations . Their results roughly agree with the data shown in Figure b, as they found that L p ≈ 5 Å for uncharged PEI and increases to ∼40 Å for fully charged chains, with the majority of this increase occurring when the chain was highly charged.…”

“…The transition from a weakly charged polyelectrolyte to a highly charged one occurred at the same protonation level in different salt conditions since the average charge–charge distance (shown in Figure a for the zero-salt condition) remained the same at different salt concentrations. R g for various values of α has also been recently calculated using molecular dynamics simulations by Basu et al for 20 mer PEI chains in 50 and 150 mM salt solutions . Despite differences in the chain lengths and force field parameters, the change in R g as a function of α for PEI chains at relatively high salt (150 mM in Basu et al, 150 and 500 mM in this study) has many consistent features in the two simulation studies.…”

“…However, the conformation transition in PEI also occurs at lower pH in lower salt, consistent with behavior reported for P2VP. Additionally, one recent experiment has provided a plot of the hydrodynamic radius of linear PEI as a function of the observed pH . In this experiment, the size of PEI in 10 and 150 mM salt increases with increasing acidity starting at a pH of slightly above 6 before plateauing near pH 3.…”

“…However, these studies examined PEI in salt-free conditions either at only three protonation states , or only when the chain was at most half protonated . Recently, Basu et al performed a series of atomistic molecular dynamic simulations of a 20 mer PEI chain at seven different protonation states and two salt concentrations and found that there is a transition in the pH- or charge-dependent behavior of PEI when it becomes more than 50–60% protonated . Here, we continue these efforts to understand the pH-dependent behavior of PEI through atomistic molecular dynamic simulations.…”

Effect of pH and Molecular Length on the Structure and Dynamics of Linear and Short-Chain Branched Poly(ethylene imine) in Dilute Solution: Scaling Laws from Detailed Molecular Dynamics Simulations

“…The increasing interest in the atomistic MD simulation of l-PEI-based systems led to the development of a new CHARMM-based atomistic force field for describing l-PEI at four different protonation fractions (0, 1/4, 1/3, and 1/2). In recent MD studies, , the effect of ionic strength (salt concentration) on the structure of l-PEI with 20 and 40 repeat units was examined. Lastly, a recent fully atomistic MD study addressed a very long hyperbranched PEI macromolecule (equivalent to 25 kDa) for which several structural properties were computed, such as the radius of gyration and the three eigenvalues of the average radius-of-gyration tensor under high-, neutral-, and low-pH conditions.…”