Yoav Atsmon-Raz

Orientations of residues along the β-arch of self-assembled amylin fibril-like structures lead to polymorphism.

Amylin is an endocrine hormone peptide that consists of 37 residues and is the main component of extracellular amyloid deposits found in the pancreas of most type 2 diabetes patients. Amylin peptides are self-assembled to form oligomers and fibrils. So far, four different molecular structures of the self-assembled amylin fibrils have been observed experimentally: two ssNMR models and two crystal models. This study reveals, for the first time, that there are four self-assembled amylin forms that differ in the orientations of the side chains along the β-arch and are all derived from the two ssNMR models. The two ssNMR models are composed of these four different self-assembled forms of amylin, and the two crystal models are composed of two different self-assembled forms of amylin. This study illustrates at the atomic level the differences among the four experimental models and proposes eight new models of self-assembled amylin that are also composed of the four different self-assembled forms of amylin. Our results show polymorphism of the self-assembled fibril-like amylin, with a slight preference of some of the newly constructed models over the experimental models. Finally, we propose that two different self-assembled fibril-like forms of amylin can interact to form a new fibril-like amylin. We investigated this argument and found that some fibril-like amylin prefers to interact to form stable fibril-like structures, whereas others disfavor it. Our work provides new insights that may suggest strategies for future pharmacological studies that aim to find ways to ameliorate the interactions between polymorphic oligomers and fibrils of amylin.

Non-Amyloid-β Component of Human α-Synuclein Oligomers Induces Formation of New Aβ Oligomers: Insight into the Mechanisms That Link Parkinson’s and Alzheimer’s Diseases

Parkinsons disease (PD) is characterized by the formation of Lewy bodies (LBs), of which their major component is the non-amyloid-β component (NAC) of α-synuclein (AS). Clinical studies have identified a link between PD and Alzheimers disease (AD), but the question of why PD patients are at risk to develop various types of dementia, such as AD, is still elusive. In vivo studies have shown that Aβ can act as a seed for NAC/AS aggregation, promoting NAC/AS aggregation and thus contributing to the etiology of PD. However, the mechanisms by which NAC/AS oligomers interact with Aβ oligomers are still elusive. This work presents the interactions between NAC oligomers and Aβ oligomers at atomic resolution by applying extensive molecular dynamics simulations for an ensemble of cross-seeded NAC-Aβ(1-42) oligomers. The main conclusions of this study are as follows: first, the cross-seeded NAC-Aβ(1-42) oligomers represent polymorphic states, yet NAC oligomers prefer to interact with Aβ(1-42) oligomers to form double-layer over single-layer conformations due to electrostatic/hydrophobic interactions; second, among the single-layer conformations, the NAC oligomers induce formation of new β-strands in Aβ(1-42) oligomers, thus leading to new Aβ oligomer structures; and third, NAC oligomers stabilize the cross-β structure of Aβ oligomers, i.e., yielding compact Aβ fibril-like structures.

A minimal length rigid helical peptide motif allows rational design of modular surfactants

Extensive work has been invested in the design of bio-inspired peptide emulsifiers. Yet, none of the formulated surfactants were based on the utilization of the robust conformation and self-assembly tendencies presented by the hydrophobins, which exhibited highest surface activity among all known proteins. Here we show that a minimalist design scheme could be employed to fabricate rigid helical peptides to mimic the rigid conformation and the helical amphipathic organization. These designer building blocks, containing natural non-coded α-aminoisobutyric acid (Aib), form superhelical assemblies as confirmed by crystallography and microscopy. The peptide sequence is amenable to structural modularity and provides the highest stable emulsions reported so far for peptide and protein emulsifiers. Moreover, we establish the ability of short peptides to perform the dual functions of emulsifiers and thickeners, a feature that typically requires synergistic effects of surfactants and polysaccharides. This work provides a different paradigm for the molecular engineering of bioemulsifiers.

The Strong Influence of Structure Polymorphism on the Conductivity of Peptide Fibrils

Peptide fibril nanostructures have been advocated as components of future biotechnology and nanotechnology devices. However, the ability to exploit the fibril functionality for applications, such as catalysis or electron transfer, depends on the formation of well-defined architectures. Fibrils made of peptides substituted with aromatic groups are described presenting efficient electron delocalization. Peptide self-assembly under various conditions produced polymorphic fibril products presenting distinctly different conductivities. This process is driven by a collective set of hydrogen bonding, electrostatic, and π-stacking interactions, and as a result it can be directed towards formation of a distinct polymorph by using the medium to enhance specific interactions rather than the others. This method facilitates the detailed characterization of different polymorphs, and allows specific conditions to be established that lead to the polymorph with the highest conductivity.

A Proposed Atomic Structure of the Self-Assembly of the Non-Amyloid-β Component of Human α-Synuclein As Derived by Computational Tools

α-Synuclein (AS) fibrils are the major hallmarks of Parkinsons disease (PD). It is known that the central domain of the 140-residue AS protein, known as the non-amyloid-β component (NAC), plays a crucial role in aggregation. The secondary structure of AS fibrils (including the NAC domain) has been proposed on the basis of solid-state nuclear magnetic resonance studies, but the atomic structure of the self-assembly of NAC (or AS itself) is still elusive. This is the first study that presents a detailed three-dimensional structure of NAC at atomic resolution. The proposed self-assembled structure of NAC consists of three β-strands connected by two turn regions. Our study shows that calculated structural parameter values of the simulated fibril-like cross-β structure of NAC are in excellent agreement with the experimental values. Moreover, the diameter dimensions of the proposed fibril-like structure are also in agreement with experimental measurements. The proposed fibril-like structure of NAC may assist in future work aimed at understanding the formation of aggregates in PD and developing compounds to modulate aggregation.

Molecular Mechanisms of the Bindings between Non-Amyloid β Component Oligomers and Amylin Oligomers

It has been suggested that the connection between amyloidogenic diseases is related to the interactions between aggregates of amyloids, which are related to type 2 diabetes and Parkinsons disease. Herein, we illustrate the interactions between amylin oligomers and non-amyloid β component (NAC) oligomers. Using molecular dynamics simulations and statistical calculations, we studied the mechanisms through which NAC oligomers interact with amylin oligomers to form NAC-amylin hetero-oligomers. Our simulations have shown that there are more than one possible pathways, which form the NAC-amylin hetero-oligomers. Our structural analyses demonstrate that the interactions in the NAC-amylin hetero-oligomers do not affect the structural features of the NAC oligomers, but they do stabilize the structures of the amylin oligomers. Taken together, our results strongly support the hypothesis that NAC oligomers may interact with amylin oligomers through several pathways, of which some pathways are more preferred because of the structural stability of the cross-seeding NAC-amylin oligomers.

Theoretical Models of Generalized Quasispecies

Theoretical modeling of quasispecies has progressed in several directions. In this chapter, we review the works of Emmanuel Tannenbaum, who, together with Eugene Shakhnovich at Harvard University and later with colleagues and students at Ben-Gurion University in Beersheva, implemented one of the more useful approaches, by progressively setting up various formulations for the quasispecies model and solving them analytically. Our review will focus on these papers that have explored new models, assumed the relevant mathematical approximations, and proceeded to analytically solve for the steady-state solutions and run stochastic simulations . When applicable, these models were related to real-life problems and situations, including changing environments, presence of chemical mutagens, evolution of cancer and tumor cells , mutations in Escherichia coli, stem cells , chromosomal instability (CIN), propagation of antibiotic drug resistance , dynamics of bacteria with plasmids , DNA proofreading mechanisms, and more.

Effect of late endosomal DOBMP lipid and traditional model lipids of electrophysiology on the anthrax toxin channel activity

Anthrax toxin action requires triggering of natural endocytic transport mechanisms whereby the binding component of the toxin forms channels (PA63) within endosomal limiting and intraluminal vesicle membranes to deliver the toxins enzymatic components into the cytosol. Membrane lipid composition varies at different stages of anthrax toxin internalization, with intraluminal vesicle membranes containing ~70% of anionic bis(monoacylglycero)phosphate lipid. Using model bilayer measurements, we show that membrane lipids can have a strong effect on the anthrax toxin channel properties, including the channel-forming activity, voltage-gating, conductance, selectivity, and enzymatic factor binding. Interestingly, the highest PA63 insertion rate was observed in bis(monoacylglycero)phosphate membranes. The molecular dynamics simulation data show that the conformational properties of the channel are different in bis(monoacylglycero)phosphate compared to PC, PE, and PS lipids. The anthrax toxin protein/lipid bilayer system can be advanced as a novel robust model to directly investigate lipid influence on membrane protein properties and protein/protein interactions.

Parameterization of Palmitoylated Cysteine, Farnesylated Cysteine, Geranylgeranylated Cysteine, and Myristoylated Glycine for the Martini Force Field

Peripheral membrane proteins go through various post-translational modifications that covalently bind fatty acid tails to specific amino acids. These post-translational modifications significantly alter the lipophilicity of the modified proteins and allow them to anchor to biological membranes. Over 1000 different proteins have been identified to date that require such membrane-protein interactions to carry out their biological functions, including members of the Src and Ras superfamilies that play key roles in cell signaling and carcinogenesis. We have used all-atom simulations with the CHARMM36 force field to parameterize four of the most common post-translational modifications for the Martini 2.2 force field: palmitoylated cysteine, farnesylated cysteine, geranylgeranylated cysteine, and myristoylated glycine. The parameters reproduce the key features of clusters of configurations of the different anchors in lipid membranes as well as the water-octanol partitioning free energies of the anchors, which are crucial for the correct reproduction of the expected biophysical behavior of peripheral membrane proteins at the membrane-water interface. Implementation in existing Martini setup tools facilitates the use of the new parameters.

The Effect of Horizontal Gene Transfer on the Dynamics of Antibiotic Drug Resistance in a Unicellular Population with a Dynamic Fitness Landscape, Repression and De-repression

Antibiotic drug resistance spreads through horizontal gene transfer (HGT) via bacterial conjugation in unicellular populations of bacteria. Consequently, the efficiency of antibiotics is limited and the expected “grace period” of novel antibiotics is typically quite short. One of the mechanisms that allow the accelerated adaptation of bacteria to antibiotics is bacterial conjugation. However, bacterial conjugation is regulated by several biological factors, with one of the most important ones being repression and derepression. In recent work, we have studied the effects that repression and de-repression on the mutation-selection balance of an HGT-enabled bacterial population in a static environment. Two of our main findings were that conjugation has a deleterious effect on the mean fitness of the population and that repression is expected to allow a restoration of the fitness cost due to plasmid hosting. Here, we consider the effect that conjugation-mediated HGT has on the speed of adaptation in a dynamic environment and the effect that repression will have on the dynamics of antibiotic drug resistance. We find that, the effect of repression is dynamic in its possible outcome, that a conjugators to non-conjugators phase transition exists in a dynamic landscape as we have previously found for a static landscape and we quantify the time required for a unicellular population to adapt to a new antibiotic in a periodically changing fitness landscape. Our results also confirmed that HGT accelerates adaptation for a population of prokaryotes which agrees with current knowledge, that HGT rates increase when a population is put under stress.