Quantitative Binding Behavior of Intrinsically Disordered Proteins to Nanoparticle Surfaces at Individual Residue Level

Abstract

The quantitative and predictive understanding how intrinsically disordered proteins (IDPs) interact with engineered nanoparticles has potentially important implications for new therapeutics as well as nanotoxicology. Based on a recently developed solution 15N NMR relaxation approach, the interactions between four representative IDPs with silica nanoparticles are reported at atomic detail. Each IDP possesses distinct binding modes, which can be quantitatively explained by the local amino‐acid residue composition using a “free residue interaction model”. The model was parameterized using the binding affinities of free proteinogenic amino acids along with long‐range effects, derived by site‐specific mutagenesis, that exponentially scale with distance along the primary sequence. The model, which is accessible through a web server, can be applied to predict the residue‐specific binding affinities of a large number of IDPs.

Functional protein dynamics on uncharted time scales detected by nanoparticle-assisted NMR spin relaxation

“…As demonstrated here, the use of slowly tumbling NPs to which a biomolecule can bind in fast exchange offers a general solution to this long-standing challenge. Rapid exchange has been observed in NMR-based NP binding studies of globular ( 33 ) and intrinsically disordered proteins ( 34 ). The binding equilibrium between NPs and proteins can be shifted by adjusting the NP concentration in the submicromolar to low micromolar range to optimize NMR line broadening (Δ R 2 < 10 s −1 with p ≈ 0.01), allowing Δ R 2 measurements with high accuracy.…”

Protein Interactions with Nanoparticle Surfaces: Highlighting Solution NMR Techniques

“…In our experience, citrate‐coated spherical AuNPs always exhibit extremely slow exchange, with no line broadening observed . On the other hand, other nanoparticle chemistries, like SiNP exhibit faster exchange, leading to a marked increase in the observed protein R 2 values . Either way, the surface‐associated protein is not directly detectable, because it experiences roughly the same (i. e. extremely slowly tumbling) as the bare nanoparticle.…”

Development of Charge-Augmented Three-Point Water Model (CAIPi3P) for Accurate Simulations of Intrinsically Disordered Proteins

“…Unlike globular proteins, intrinsically disordered proteins (IDPs) do not have a proper hydrophobic core. As such, long-range electrostatic interactions play an important role in defining of IDP behaviour [ 19 , 20 ]. Therefore, to accurately predict the dynamics of IDPs from the atomistic molecular simulations, the water interactions with the environment and with the solute of interest need to be re-calibrated.…”

“…IDPs have unordered structures in aqueous solution, and while either dehydrated or interacting with lipid membranes, they exhibit increased amounts of ordered secondary structures [ 18 ]. This clearly shows that IDPs are highly sensitive to solvation effects [ 19 , 20 ] and suggests that focusing on the improvement of the water models used in the simulations may offer a more accurate yet computationally feasible framework for reliable simulations of this class of proteins.…”