Graphitic nanoflakes modulate the structure and binding of human amylin.

Human amylin is an inherently disordered protein whose ability to form amyloid fibrils is linked to the onset of type II diabetes. Graphitic nanomaterials have potential in managing amyloid diseases as they can disrupt protein aggregation processes in biological settings, but optimising these materials to prevent fibrillation is challenging. Here, we employ bias-exchange molecular dynamics simulations to systematically study the structure and adsorption preferences of amylin on graphitic nanoflakes that vary in their physical dimensions and surface functionalisation.

Atomic Scale Structure of Self-Assembled Lipidated Peptide Nanomaterials.

β-Peptides have great potential as novel biomaterials and therapeutic agents, due to their unique ability to self-assemble into low dimensional nanostructures, and their resistance to enzymatic degradation in vivo. However, the self-assembly mechanisms of β-peptides, which possess increased flexibility due to the extra backbone methylene groups present within the constituent β-amino acids, are not well understood due to inherent difficulties of observing their bottom-up growth pathway experimentally. A computational approach is presented for the bottom-up modelling of the self-assembled lipidated β-peptides, from monomers, to oligomers, to supramolecular low-dimensional nanostructures, in all-atom detail.

Translocation of silica nanospheres through giant unilamellar vesicles (GUVs) induced by a high frequency electromagnetic field.

Membrane model systems capable of mimicking live cell membranes were used for the first time in studying the effects arising from electromagnetic fields (EMFs) of 18 GHz where membrane permeability was observed following exposure. A present lack of understanding of the mechanisms that drive such a rapid change in membrane permeabilization as well as any structural or dynamic changes imparted on biomolecules affected by high-frequency electromagnetic irradiation limits the use of 18 GHz EMFs in biomedical applications. A phospholipid, 1,2-dioleoyl--glycero-3-phosphocholine (DOPC) labelled with a fluorescent marker 1,2-dioleoyl--glycero-3-phosphoethanolamine--(lissamine rhodamine B sulfonyl) (rhodamine-DOPE) was used in constructing the giant unilamellar vesicles (GUVs).

Compact Peptoid Molecular Brushes for Nanoparticle Stabilization.

Controlling the interfaces and interactions of colloidal nanoparticles (NPs) via tethered molecular moieties is crucial for NP applications in engineered nanomaterials, optics, catalysis, and nanomedicine. Despite a broad range of molecular types explored, there is a need for a flexible approach to rationally vary the chemistry and structure of these interfacial molecules for controlling NP stability in diverse environments, while maintaining a small size of the NP molecular shell. Here, we demonstrate that low-molecular-weight, bifunctional comb-shaped, and sequence-defined peptoids can effectively stabilize gold NPs (AuNPs).

Electromagnetic bioeffects: a multiscale molecular simulation perspective.

Electromagnetic bioeffects remain an enigma from both the experimental and theoretical perspectives despite the ubiquitous presence of related technologies in contemporary life. Multiscale computational modelling can provide valuable insights into biochemical systems and predict how they will be perturbed by external stimuli. At a microscopic level, it can be used to determine what (sub)molecular scale reactions various stimuli might induce; at a macroscopic level, it can be used to examine how these changes affect dynamic behaviour of essential molecules within the crowded biomolecular milieu in living tissues.

An Active Site Inhibitor Induces Conformational Penalties for ACE2 Recognition by the Spike Protein of SARS-CoV-2.

The novel RNA virus, severe acute respiratory syndrome coronavirus II (SARS-CoV-2), is currently the leading cause of mortality in 2020, having led to over 1.6 million deaths and infecting over 75 million people worldwide by December 2020. While vaccination has started and several clinical trials for a number of vaccines are currently underway, there is a pressing need for a cure for those already infected with the virus.

DNA origami protection and molecular interfacing through engineered sequence-defined peptoids.

DNA nanotechnology has established approaches for designing programmable and precisely controlled nanoscale architectures through specific Watson-Crick base-pairing, molecular plasticity, and intermolecular connectivity. In particular, superior control over DNA origami structures could be beneficial for biomedical applications, including biosensing, in vivo imaging, and drug and gene delivery. However, protecting DNA origami structures in complex biological fluids while preserving their structural characteristics remains a major challenge for enabling these applications.

Effects of Size and Functionalization on the Structure and Properties of Graphene Oxide Nanoflakes: An in Silico Investigation.

Graphitic nanoparticles, specifically, graphene oxide (GO) nanoflakes, are of major interest in the field of nanotechnology, with potential applications ranging from drug delivery systems to energy storage devices. These applications are possible largely because of the properties imparted by various functional groups attached to the GO surface by relatively simple production methods compared to pristine graphene. We investigated how varying the size and oxidation of GO flakes can affect their structural and dynamic properties in an aqueous solution.

Surface Dynamics and Ligand-Core Interactions of Quantum Sized Photoluminescent Gold Nanoclusters.

Quantum-sized metallic clusters protected by biological ligands represent a new class of luminescent materials; yet the understanding of structural information and photoluminescence origin of these ultrasmall clusters remains a challenge. Herein we systematically study the surface ligand dynamics and ligand-metal core interactions of peptide-protected gold nanoclusters (AuNCs) with combined experimental characterizations and theoretical molecular simulations. We show that the peptide sequence plays an important role in determining the surface peptide structuring, interfacial water dynamics and ligand-Au core interaction, which can be tailored by controlling peptide acetylation, constituent amino acid electron donating/withdrawing capacity, aromaticity/hydrophobicity and by adjusting environmental pH.

Identifying the Coiled-Coil Triple Helix Structure of β-Peptide Nanofibers at Atomic Resolution.

Peptide self-assembly represents a powerful bottom-up approach to the fabrication of nanomaterials. β-Peptides are non-natural peptides composed entirely of β-amino acids, which have an extra methylene in the backbone, and we reported fibers derived from the self-assembly of β-peptides that adopt 14-helical structures. β-Peptide assemblies represent a class of stable nanomaterials that can be used to generate bio- and magneto-responsive materials with proteolytic stability.

Polymorphism in disease-related apolipoprotein C-II amyloid fibrils: a structural model for rod-like fibrils.

Human apolipoprotein (apo) C-II is one of several plasma apolipoproteins that form amyloid deposits in vivo and is an independent risk factor for cardiovascular disease. Lipid-free apoC-II readily self-assembles into twisted-ribbon amyloid fibrils but forms straight, rod-like amyloid fibrils in the presence of low concentrations of micellar phospholipids. Charge mutations exerted significantly different effects on rod-like fibril formation compared to their effects on twisted-ribbon fibril formation.

Effects of forcefield and sampling method in all-atom simulations of inherently disordered proteins: Application to conformational preferences of human amylin.

Although several computational modelling studies have investigated the conformational behaviour of inherently disordered protein (IDP) amylin, discrepancies in identifying its preferred solution conformations still exist between various forcefields and sampling methods used. Human islet amyloid polypeptide has long been a subject of research, both experimentally and theoretically, as the aggregation of this protein is believed to be the lead cause of type-II diabetes. In this work, we present a systematic forcefield assessment using one of the most advanced non-biased sampling techniques, Replica Exchange with Solute Tempering (REST2), by comparing the secondary structure preferences of monomeric amylin in solution.

Facet-Dependent Interactions of Islet Amyloid Polypeptide with Gold Nanoparticles: Implications for Fibril Formation and Peptide-Induced Lipid Membrane Disruption.

A comprehensive understanding of the mechanisms of interaction between proteins or peptides and nanomaterials is crucial for the development of nanomaterial-based diagnostics and therapeutics. In this work, we systematically explored the interactions between citrate-capped gold nanoparticles (AuNPs) and islet amyloid polypeptide (IAPP), a 37-amino acid peptide hormone co-secreted with insulin from the pancreatic islet. We utilized diffusion-ordered spectroscopy, isothermal titration calorimetry, localized surface plasmon resonance spectroscopy, gel electrophoresis, atomic force microscopy, transmission electron microscopy (TEM), and molecular dynamics (MD) simulations to systematically elucidate the underlying mechanism of the IAPP-AuNP interactions.

Intra- and Intersubunit Ion-Pair Interactions Determine the Ability of Apolipoprotein C-II Mutants To Form Hybrid Amyloid Fibrils.

The apolipoprotein family is structurally defined by amphipathic α-helical regions that interact with lipid surfaces. In the absence of lipid, human apolipoprotein (apo) C-II also forms well-defined amyloid fibrils with cross-β structure. Formation of this β-structure is accompanied by the burial of two charged residues, K30 and D69, that form an ion-pair within the amyloid fibril core.

Bioelectromagnetics Research within an Australian Context: The Australian Centre for Electromagnetic Bioeffects Research (ACEBR).

Mobile phone subscriptions continue to increase across the world, with the electromagnetic fields (EMF) emitted by these devices, as well as by related technologies such as Wi-Fi and smart meters, now ubiquitous. This increase in use and consequent exposure to mobile communication (MC)-related EMF has led to concern about possible health effects that could arise from this exposure. Although much research has been conducted since the introduction of these technologies, uncertainty about the impact on health remains.

Solution Conditions Affect the Ability of the K30D Mutation To Prevent Amyloid Fibril Formation by Apolipoprotein C-II: Insights from Experiments and Theoretical Simulations.

Apolipoproteins form amphipathic helical structures that bind lipid surfaces. Paradoxically, lipid-free apolipoproteins display a strong propensity to form cross-β structure and self-associate into disease-related amyloid fibrils. Studies of apolipoprotein C-II (apoC-II) amyloid fibrils suggest that a K30-D69 ion pair accounts for the dual abilities to form helix and cross-β structure.

Gold Nanoparticles: Understanding and Designing the Gold-Bio Interface: Insights from Simulations (Small 18/2016).

Computational modeling is a virtual microscope providing molecular insight into the complex interactions occurring at nano-bio interfaces. The image shows the atomistic landscape of a peptide-adlayer on gold nanoparticles, providing the physicochemical information needed to tailor the design of efficient colorimetric biosensors. The successes and challenges of theoretical simulations in facilitating gold nanomaterial design for biomedicine are reviewed on page 2395 by I.

Understanding and Designing the Gold-Bio Interface: Insights from Simulations.

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.

Electromagnetic-field effects on structure and dynamics of amyloidogenic peptides.

Electromagnetic fields (EMFs) are ever-present, and so is the need to better understand their influence on human health and biological matter in general. The interaction between a molecular system and external EMF can alter the structure, and dynamical behaviour, and, hence, biological function of proteins with uncertain health consequences. This urges a detailed investigation of EMF-induced effects on basic protein biophysics.

Hydrogen/Deuterium Exchange and Molecular Dynamics Analysis of Amyloid Fibrils Formed by a D69K Charge-Pair Mutant of Human Apolipoprotein C-II.

Plasma apolipoproteins form amphipathic α helices in lipid environments but in the lipid-free state show a high propensity to form β structure and self-associate into amyloid fibrils. The widespread occurrence of apolipoproteins in amyloid plaques suggests disease-related roles, specifically in atherosclerosis. To reconcile the dual abilities of apolipoproteins to form either α helices or cross-β sheet structures, we examined fibrils formed by human apolipoprotein C-II (apoC-II).

Surface presentation of functional peptides in solution determines cell internalization efficiency of TAT conjugated nanoparticles.

Functionalizing nanoparticles with cell-penetrating peptides is a popular choice for cellular delivery. We investigated the effects of TAT peptide concentration and arrangement in solution on functionalized nanoparticles' efficacy for membrane permeation. We found that cell internalization correlates with the positive charge distribution achieved prior to nanoparticle encountering interactions with membrane.

Dimensionality of carbon nanomaterials determines the binding and dynamics of amyloidogenic peptides: multiscale theoretical simulations.

Experimental studies have demonstrated that nanoparticles can affect the rate of protein self-assembly, possibly interfering with the development of protein misfolding diseases such as Alzheimer's, Parkinson's and prion disease caused by aggregation and fibril formation of amyloid-prone proteins. We employ classical molecular dynamics simulations and large-scale density functional theory calculations to investigate the effects of nanomaterials on the structure, dynamics and binding of an amyloidogenic peptide apoC-II(60-70). We show that the binding affinity of this peptide to carbonaceous nanomaterials such as C60, nanotubes and graphene decreases with increasing nanoparticle curvature.

"Janus" cyclic peptides: a new approach to amyloid fibril inhibition?

Cyclic peptides are increasingly being shown as powerful inhibitors of fibril formation, and have the potential to be therapeutic agents for combating many debilitating amyloid-related diseases. One such example is a cyclic peptide derivative from the human apolipoprotein C-II, which has the ability to inhibit fibril formation by the fibrillogenic peptide apoC-II(60-70). Using classical molecular dynamics and electronic structure calculations, we were able to provide insight into the interaction between the amyloidogenic peptide apoC-II(60-70) and its cyclic derivative, cyc(60-70).

A cyclic peptide inhibitor of apoC-II peptide fibril formation: mechanistic insight from NMR and molecular dynamics analysis.

The misfolding and aggregation of proteins to form amyloid fibrils is a characteristic feature of several common age-related diseases. Agents that directly inhibit formation of amyloid fibrils represent one approach to combating these diseases. We have investigated the potential of a cyclic peptide to inhibit fibril formation by fibrillogenic peptides from human apolipoprotein C-II (apoC-II).