Biology subjects

Bevan, D. R.

Publications and source records attributed to Bevan, D. R..

3 recordsLinked to original sources

bioRxiv2021

Insight into Cross-Amyloid Interactions and Morphologies: Molecular Dynamics Simulations of Model Peptide Fragments of Amyloid-β (Aβ16-22) and Islet Amyloid Polypeptide (IAPP20-29)

Amyloid-beta (A{beta}) and islet amyloid polypeptide (IAPP) are small peptides, classified as amyloids, that have the potential to self-assemble and form cytotoxic species, such as small soluble oligomers and large insoluble fibrils. The formation of A{beta} aggregates facilitates the progression of Alzheimers disease (AD), while IAPP aggregates induce pancreatic {beta}-cell apoptosis, leading to exacerbation of Type 2 diabetes (T2D). Cross-amyloid interactions between A{beta} and IAPP have been described both in vivo and in vitro, implying the role of A{beta} or IAPP as modulators of cytotoxic self-aggregation of each peptide, and suggesting that A{beta}-IAPP interactions are a potential molecular link between AD and T2D. Using molecular dynamics simulations, "hot spot" regions of the two peptides were studied to understand the formation of hexamers in a heterogenous and homogenous peptide-containing environment. Systems of only A{beta}(16-22) peptides formed antiparallel, {beta}-barrel-like structures, while systems of only IAPP(20-29) peptides formed stacked, parallel beta strands and had relatively unstable aggregation structures after 2 s of simulation time. Systems containing both A{beta} and IAPP (1:1 ratio) hexamers showed antiparallel, {beta}-barrel-like structures, with an interdigitated arrangement of A{beta}(16-22) and IAPP(20-29). These {beta}-barrel structures have features of cytotoxic amyloid species identified in previous literature. Ultimately, this work seeks to provide atomistic insight into both the mechanism behind cross-amyloid interactions and structural morphologies of these toxic amyloid species. Statement of SignificanceMolecular knowledge, biophysical characterization, structural morphologies, and formation pathways of amyloid oligomers - specifically low-molecular weight, cross-amyloid oligomers - remain preliminary and undefined. Characterizing interactions between homogenous and heterogenous amyloid oligomers is of great interest given that certain oligomer morphologies contribute to cytotoxicity, eventually resulting in comorbid diseases such as Alzheimers disease (AD) and Type 2 Diabetes Mellitus (T2DM). Utilizing model systems (e.g., fragments of full-length peptides) and molecular dynamics (MD) simulations to probe the biophysical underpinnings of cross-amyloid oligomer structures is the first step in understanding the dynamics, stability, and potential modes of cytotoxicity of these species, providing important insights into targetable biomolecular structures.

biochemistry↗

bioRxiv2020

Catechol-Containing Compounds are a Broad Class of Amyloid Inhibitors: II. Rosmarinic Acid Potently Detoxifies Amylin Amyloid and Ameliorates Diabetic Pathology in HIP Rats

Protein aggregation is associated with a large number of human protein misfolding diseases, yet FDA-approved drugs are currently not available. Amylin amyloid and plaque depositions in the pancreas are hallmark features of type 2 diabetes. Moreover, these amyloid deposits are implicated in the pathogenesis of diabetic complications such as neurodegeneration. We recently discovered that catechols and redox-related quinones/ anthraquinones represent a broad class of protein aggregation inhibitors. Further screening of a targeted library of natural compounds in complementary medicine that were enriched with catechol-containing compounds identified rosmarinic acid as a potent inhibitor of amylin aggregation (estimated inhibitory concentration IC50 = 200-300 nM). Structure-function relationship analysis of rosmarinic acid showed the additive effects of two catechol-containing components of the RA molecule. We further showed that RA does not reverse fibrillation back to monomeric amylin, but lead to non-toxic, remodeled protein aggregates. Rosmarinic acid has significant ex vivo efficacy in reducing human amylin oligomer levels in HIP rat sera as well as in sera from diabetic patients. In vivo efficacy studies of rosmarinic acid treatment with the diabetic HIP rat model demonstrated significant reduction in amyloid islet deposition and strong mitigation of diabetic pathology. Our work provides new in vitro molecular mechanisms and in vivo efficacy insights for a model nutraceutical agent against type 2 diabetes and other aging-related protein misfolding diseases.

pharmacology and toxicology↗

bioRxiv2018

HIV-1 Env gp41 Transmembrane Domain Dynamics are Modulated by Lipid, Water, and Ion Interactions

The gp41 transmembrane domain (TMD) of the envelope glycoprotein (Env) of the human immunodeficiency virus (HIV) modulates the conformation of the viral envelope spike, the only druggable target on the surface of the virion. Understanding of TMD dynamics is needed to better probe and target Env with small molecule and antibody therapies. However, little is known about TMD dynamics due to difficulties in describing native membrane properties. Here, we performed atomistic molecular dynamics simulations of a trimeric, prefusion TMD in a model, asymmetric viral membrane that mimics the native viral envelope. We found that water and chloride ions permeated the membrane and interacted with the highly conserved arginine bundle, (R696)3, at the center of the membrane and influenced TMD stability by creating a network of hydrogen bonds and electrostatic interactions. We propose that this (R696)3 - water - anion network plays an important role in viral fusion with the host cell by modulating protein conformational changes within the membrane. Additionally, R683 and R707 at the exofacial and cytofacial membrane-water interfaces, respectively, are anchored in the lipid headgroup region and serve as a junction point for stabilization of the termini. The membrane thins as a result of the tilting of the TMD trimer, with nearby lipids increasing in volume, leading to an entropic driving force for TMD conformational change. These results provide additional detail and perspective on the influence of certain lipid types on TMD dynamics and rationale for targeting key residues of the TMD for therapeutic design. These insights into the molecular details of TMD membrane anchoring will build towards a greater understanding of dynamics that lead to viral fusion with the host cell.

biophysics↗