Society is increasingly exposed to nanoparticles as they are ubiquitous in nature and introduced as man-made air pollutants and as functional ingredients in cosmetic products as well as in nanomedicine. Nanoparticles differ in size, shape and material properties. In addition to their intended function, the side effects on biochemical processes in organisms remain unclear. Nanoparticles can significantly influence the nucleation and aggregation process of peptides. The development of several neurodegenerative diseases, such as Alzheimer's disease, is related to the aggregation of peptides into amyloid fibrils. However, there is no comprehensive or universal mechanism to predict or explain apparent acceleration or inhibition of these aggregation processes. In this work, selected studies and possible mechanisms for amyloid peptide nucleation and aggregation, in the presence of nanoparticles, are highlighted. These studies are discussed in the context of recent data from our group on the role of gold nanoparticles in amyloid peptide aggregation using experimental methods and large-scale molecular dynamics simulations. A complex interplay of the surface properties of the nanoparticles, the properties of the peptides, as well as the resulting forces between both the nanoparticles and the peptides, appear to determine whether amyloid peptide aggregation is influenced, catalysed or inhibited by the presence of nanoparticles.

Impact of nanoparticles on amyloid peptide and protein aggregation: a review with a focus on gold nanoparticles

The question of how amyloid fibril formation is influenced by surfaces is crucial for a detailed understanding of the process in vivo. We applied a combination of kinetic experiments and molecular dynamics simulations to elucidate how (model) surfaces influence fibril formation of the amyloid-forming sequences of prion protein SUP35 and human islet amyloid polypeptide. The kinetic data suggest that structural reorganization of the initial peptide corona around colloidal gold nanoparticles is the rate-limiting step. The molecular dynamics simulations reveal that partial physisorption to the surface results in the formation of aligned monolayers, which stimulate the formation of parallel, critical oligomers. The general mechanism implies that the competition between the underlying peptide–peptide and peptide–surface interactions must strike a balance to accelerate fibril formation.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.201605151

Gold-Induced Fibril Growth: The Mechanism of Surface-Facilitated Amyloid Aggregation.

Gold nanoparticles (AuNPs) are an integral part of many exciting and novel biomedical applications, sparking the urgent need for a thorough understanding of the physicochemical interactions occurring between these inorganic materials, their functional layers, and the biological species they interact with. Computational approaches are instrumental in providing the necessary molecular insight into the structural and dynamic behavior of the Au-bio interface with spatial and temporal resolutions not yet achievable in the laboratory, and are able to facilitate a rational approach to AuNP design for specific applications. A perspective of the current successes and challenges associated with the multiscale computational treatment of Au-bio interfacial systems, from electronic structure calculations to force field methods, is provided to illustrate the links between different approaches and their relationship to experiment and applications.

Understanding and Designing the Gold–Bio Interface: Insights from Simulations

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Mechanistic insights into the size-dependent effects of nanoparticles on inhibiting and accelerating amyloid fibril formation.

Control over supramolecular recognition between proteins and nanoparticles (NPs) is of fundamental importance in therapeutic applications and sensor development. Most NP-protein binding approaches use 'tags' such as biotin or His-tags to provide high affinity; protein surface recognition provides a versatile alternative strategy. Generating high affinity NP-protein interactions is challenging however, due to dielectric screening at physiological ionic strengths. We report here the co-engineering of nanoparticles and protein to provide high affinity binding. In this strategy, 'supercharged' proteins provide enhanced interfacial electrostatic interactions with complementarily charged nanoparticles, generating high affinity complexes. Significantly, the co-engineered protein-nanoparticle assemblies feature high binding affinity even at physiologically relevant ionic strength conditions. Computational studies identify both hydrophobic and electrostatic interactions as drivers for these high affinity NP-protein complexes.

High affinity protein surface binding through co-engineering of nanoparticles and proteins.

Protein-nanoparticle associations have important applications in nanoscience and nanotechnology but the recognition mechanisms and the determinants of specificity are still poorly understood at the microscopic level. Crucial questions remain open, related to the association mechanisms, control of bindingevents,andpreservationoffunctionality.Goldisapromisingmaterial in nanoparticles for nanobiotechnology applications because of the ease of its functionalization and its tunable optical properties. We present a concise overview of recent computational modeling advances which were pursued in the quest for a theoretical framework elucidating the association mechanisms and the ability to design and control the recognition events of a specific class of systems, namely, interfaces between polypeptides/proteins and a gold surface in the presence of water. We select two different methodological advances, the first related to the effect of surfactants covering the surface of nanoparticles and altering their interactions with proteins and the second related to the immobilization of proteins on inorganic surfaces and conserving their functionality. Both cases, demonstrate how the understanding of the polypeptide-surface coupling mechanisms is essential to the control of the processandexploitationforbiotechnologicalandnanotechnologicalpurposes.

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Laura Zanetti Polzi

Papers

Computational Strategies for Protein-Surface and Protein-Nanoparticle Interactions