Large Local Internal Stress in an Elastically Bent Molecular Crystal Revealed by Raman Shifts.

The structural dynamics involved in the mechanical flexibility of molecular crystals and the internal stress in such flexible materials remain obscure. Here, the study reports an elastically bending lipidated molecular crystal that shows systematic shifts in characteristic vibrational frequencies across the bent crystal region - revealing the nature of structural changes during bending and the local internal stress distribution. The blueshifts in the bond stretching modes (such as C═O and C-H modes) in the inner arc region and redshifts in the outer arc region of the bent crystals observed via micro-Raman mapping are counterintuitive to the bending models based on intermolecular hydrogen bonds. Correlating these shifts with the trends observed from high-pressure Raman studies on the crystal reveals the local stress difference between the inner arc and outer arc regions of the bent crystal to be ≈2 GPa, more than an order of magnitude higher than the previously proposed value in elastically bending crystals. High local internal stress can have direct ramifications on the properties of molecular piezoelectric energy harvesters, actuators, semiconductors, and flexible optoelectronic materials.

Bispidine as a Versatile Scaffold: From Topological Hosts to Transmembrane Transporters.

The development of designer topological structures is a synthetically challenging endeavor. We present herein bispidine as a platform for the design of molecules with various topologies and functions. The bispidine-based acyclic molecule, which shows intriguing S-shape topology, is discussed. Single-crystal X-ray diffraction studies revealed that this molecule exists in the solid state as two conformational enantiomers. In addition, bispidine-based designer macrocycles were synthesized and investigated for ionophoric properties. Patch clamp experiments revealed that these macrocycles transport both anions and cations non-specifically with at least tenfold higher chloride conductance over the cations under the given experimental conditions. Ultramicroscopy and single-crystal X-ray crystallographic studies indicated that the self-assembling macrocycle forms a tubular assembly. Our design highlights the use of unconventional dihydrogen interactions in nanotube fabrication.

Fluorescence by self-assembly: autofluorescent peptide vesicles and fibers.

A series of oxidized cysteinyl peptides ([P-Cys-X-OMe]2; P = Boc or H; X = Trp or Glu) showed vesicular and fibrillar assemblies. The anatomy of the self-assembled vesicles from the water-soluble cystine peptide [Cys-Trp-OMe]2 (1a) has been investigated by using various fluorescent probes such as ammonium 8-anilinonaphthalene-1-sulfonate, Nile Red and pyrene. The morphological characterization was carried out by fluorescence lifetime imaging microscopy (FLIM) and super resolution-structured illumination microscopy (SR-SIM) utilizing the autofluorescence of the vesicles stemming from the self-assembly. The self-assembled structures are also observed in solution as evident from the quantitative phase images obtained using a dual-mode digital holographic microscope (DHM) system. Present investigations show that the self-assembly is enthalpy- and entropy-driven in the aqueous medium. Based on the CD spectral studies, we proposed that 1a organizes into vesicles through the sequestration of indole units. We observed that the solutions of dipeptides 1a-b exhibit autofluorescence in the blue region upon excitation at a wavelength >350 nm. Detailed spectroscopic studies on the peptides lacking tryptophan 2a-b unequivocally showed that the autofluorescence stems exclusively from peptide aggregation. Our experimental results with appropriate controls revealed that the clustering of carbonyl chromophores is central to autofluorescence. Autofluorescence was also used to probe the vesicle formation without using any external fluorescent probe. To the best of our knowledge, this is the first report on autofluorescent vesicles formed by the spontaneous association of dipeptides. We also found that the vesicles formed by 1a can act as a host for guests like C60. The biocompatibility and biodegradability of these peptides along with the autofluorescent nature and guest binding ability of peptide-based vesicles offer numerous applications in the biomedical area.

Pseudopeptosomes: non-lipidated vesicular assemblies from bispidine-appended pseudopeptides.

We report a novel molecular topology-based approach for creating reproducible vesicular assemblies in different solvent environments (including aqueous) using specifically designed pseudopeptides. Deviating from the classical "polar head group and hydrophobic tail" model of amphiphiles, we showed (reversible) self-assembly of synthesized pseudopeptides into vesicles. Naming these new type/class of vesicles "pseudopetosomes", we characterized them by high-resolution microscopy (scanning electron, transmission electron, atomic force, epifluorescence and confocal) along with dynamic light scattering. While accounting for hydropathy index of the constituent amino acids (side chains) of pseudopeptides, we probed molecular interactions, resulting in assembly of pseudopeptosomes by spectroscopy (fourier-transform infrared and fluorescence). Molecular characterization by X-ray crystallography and circular dichroism revealed "tryptophan (Trp)-Zip" arrangements and/or hydrogen-bonded one-dimensional assembly depending on specific pseudopeptides and solvent environments. Our data indicated that pseudopeptosomes are formed in solutions by self-assembly of bispidine pseudopeptides (of Trp, leucine and alanine amino-acid constituents) into sheets that transform into vesicular structures. Thus, we showed that assembly of pseudopeptosomes utilizes the full spectrum of all four weak interactions essential in biological systems. Our findings have direct implications in chemical and synthetic biology, but may also provide a new avenue of investigations on origins of life via pseudopeptosome-like assemblies. We also showed that these designer peptides can act as carriers for cellular transport.

Expanded triazolophanes: a topological analysis of vesicular assembly.

Triazolophanes with larger ring sizes such as 40- and 42- were designed and synthesized. Ultramicroscopic studies on a variety of expanded triazolophanes and larger acyclic systems revealed vesicular self-assembly. The role of molecular topology on vesicular assembly was systematically investigated by studying a series of molecules with increasing curvature.

Bispidine as a promising scaffold for designing molecular machines.

The development of artificial molecular machines is a challenging endeavor. Herein, we have synthesized a series of bispidine diamides D1-D6 that exhibit rotation reminiscent of a motor motion. Dynamic NMR, X-ray diffraction, quantum mechanical calculations, and molecular dynamics simulations provided insights into their rotational dynamics. All the diamides D1-D6 exhibited mutually independent rotation around the two bispidine arms. However, the rate of rotation and the presence or absence of directionality in amide bond rotation were found to depend on the solvent, temperature, and nature of substitution on the amide carbonyl. These engineered systems may aid in the development of biologically relevant synthetic molecular motors. Studies on homochiral and heterochiral bispidine-peptides revealed that the direction of rotation can be controlled by chirality and the nature of the amino acid.

Highly Efficient Intramolecular Excimer Formation in a Disulfide-Linked Dipyrenyl Compound: Proton Recognition and Fluidity Assessment.

Intramolecular excimer formation has been utilized extensively in chemical sciences, especially to probe solvation within complex media as well as to assess physicochemical properties of the solubilizing milieu. Pyrene has been employed extensively as a fluorescence probe for this purpose due to its favorable multidimensional fluorescence properties. Termini-capped dipyrenyl scaffolds possessing various functionalities comprise the majority of such compounds. A new both end-tagged dipyrenyl compound DTP is designed and synthesized, which exhibits significantly high intramolecular excimer formation efficiency in polar solvents. The presence of a -NH-(CO)- and/or -S-S- functionality on the chain linking the two pyrenyl groups facilitates intramolecular excimer formation. Excited-state emission intensity decay reveals that the excimer formation exclusively takes place in the excited state with only one excimer conformation. The rate constant of excimer formation is found to be higher for DTP as compared to a similar compound with an alkyl backbone. The dependence of the excimer formation on the solvent (protic versus aprotic) as well as on temperature reveals further insights into the excimer formation process. The excimer formation by DTP is found to be highly sensitive to the presence of H+: the relative excimer formation efficiency decreases drastically in the presence of a small amount of H+ (∼10-5 M). Further, the recognition of protons by DTP via intramolecular excimer formation is also observed to be highly selective in nature. Based on the observation that both the excimer formation efficiency and kinetics depend on the viscosity of the solubilizing milieu, fluidity assessment of the (dimethyl sulfoxide + acetonitrile) mixture was carried out using DTP. Further, DTP is found to be an effective probe for the assessment of the amount of water in the ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl) imide as well as in a deep eutectic solvent composed of choline chloride and urea in a 1:2 mol ratio. Highly efficient and rapid intramolecular excimer formation not only establishes DTP as a useful and versatile probe but also offers strategic pathways for designing effective excimer-forming compounds.

Molecular Insights into the Inhibition of Dialysis-Related ß2m Amyloidosis Orchestrated by a Bispidine Peptidomimetic Analogue.

Dialysis-related amyloidosis (DRA) is considered an inescapable consequence of renal failure. Upon prolonged hemodialysis, it involves accumulation of toxic ß2-microglobulin (ß2m) amyloids in bones and joints. Current treatment methods are plagued with high cost, low specificity, and low capacity. Through our in vitro and in cellulo studies, we introduce a peptidomimetic-based approach to help develop future therapeutics against DRA. Our study reports the ability of a nontoxic, core-modified, bispidine peptidomimetic analogue "B(LVI)2" to inhibit acid-induced amyloid fibrillation of ß2m (Hß2m). Using thioflavin-T, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and transmission electron microscopy analysis, we demonstrate that B(LVI)2 delays aggregation lag time of Hß2m amyloid fibrillation and reduces the yield of Hß2m amyloid fibrils in a dose-dependent manner. Our findings suggest a B(LVI)2-orchestrated alteration in the route of Hß2m amyloid fibrillation resulting in the formation of noncytotoxic, morphologically distinct amyloid-like species. Circular dichroism data show gradual sequestration of Hß2m species in a soluble nonamyloidogenic noncytotoxic conformation in the presence of B(LVI)2. Dynamic light scattering measurements indicate incompetence of Hß2m species in the presence of B(LVI)2 to undergo amyloid-competent intermolecular associations. Overall, our study reports the antifibrillation property of a novel peptidomimetic with the potential to bring a paradigm shift in therapeutic approaches against DRA.

Tailoring of Peptide Vesicles: A Bottom-Up Chemical Approach.

Spherical ordering from small molecules is a subject of intense interest to chemists. The inherent capability of amphiphiles to assemble spontaneously is the unique feature of the evolutionary process of life. Self-assembly is prevalent in biology and has attracted the interest of scientists across several disciplines. This is because scientists have realized that nature has extensively used this inherent organizational power contained in the molecules. Judicious use of the self-assembly principle is the cornerstone of nature's exotic assemblies. These exotic assemblies lead to unimaginable functions in biology that might not have been predicted from the monomer building blocks alone. Recently, a number of chemical systems that self-assemble in aqueous or organic solvents to form vesicles were reported. This account provides advances made from our laboratory toward designing and understanding the mechanism of formation of spherical vesicular assembly. A bottom-up approach for the de novo design of vesicles using nonlipidated molecular architecture will be a paradigm shift in vesicular research. Vesicles act as a protocell model for studying the origin and evolution of cellular life. They could also act as excellent model systems for studying the fusion of cells and membrane transport. Self-assembled vesicles have enormous potential for several applications such as drug and biomolecule delivery to cells and in materials science. These aspects along with the dynamic nature of vesicular assembly have attracted researchers to the study of spherical assemblies. The common belief was that the molecules that form vesicles must have one polar head and two hydrophobic tails. All attempts to synthesize vesicles are by mimicking nature's strategy, which mainly involves the self-assembly of lipid amphiphiles through a bilayer-like arrangement. Pseudopeptide-based molecules with the ability to form vesicles have changed this long-standing notion. In addition to chemical and medical applications, these peptide vesicles could act as models for protocells, membrane fusion, and the study of the vesiculation mechanism. This Account highlights the progress made toward a heuristic approach to the de novo design of vesicles using pseudopeptides as building blocks.A large number of diverse classes of pseudopeptides showed vesicular assembly. Various acyclic and cyclic molecules were designed and synthesized that showed spherical vesicular assembly. Cystine-based macrocyclic peptides showed drug encapsulation and release. Polymersomes with unusual topology, self-assembling tripodal ligands, and molecules containing amino acids such as lysine, leucine, cystine, and serine were synthesized. The incorporation of a wide variety of amino acids in the vesicle-forming peptides could enhance their scope and applications. The mechanism of vesiculation was also investigated using these designer molecules.

Liquid crystal droplet design by using pseudopeptidic bottlebrush polymer additives.

Liquid crystal (LC) droplets are promising candidates for sensing applications due to their high sensitivity to surface anchoring changes, resulting in readily detectable optical effects. Herein, we have designed and synthesized amino acid-based bottlebrush polymers and investigated their impact on LC director configurations in the droplets. The pseudopeptidic bottlebrush polymers with an aromatic (phenyl) and aliphatic appendages are synthesized using ring-opening metathesis polymerization (ROMP). Polymer dispersed liquid crystal (PDLC) samples are prepared by employing pseudopeptidic bottlebrush polymers and 4-cyano-4'-pentylbiphenyl (5CB) LC via solvent-induced phase separation (SIPS) technique. Due to π-π stacking, the phenyl group favours radial configuration, whereas the repulsion between 5CB and aliphatic groups induces molecular alignment leading to bipolar droplet arrangement. The impact of various pendant groups attached to the polymer on the prepared PDLC sample's surface characteristics and free energy components is illustrated. The sensing capability of 5CB dispersed in pseudopeptidic bottlebrush polymers for various pH solutions is investigated using polarizing optical microscopy (POM). The PDLC samples are moderately permeable to water and sensitive to different pH solutions. The results demonstrate a simplified and straightforward approach for preparing LC-based biosensors and chemical sensors.

Designer peptides as versatile building blocks for functional materials.

Peptides and pseudopeptides show distinct self-assembled nanostructures such as fibers, nanotubes, vesicles, micelles, toroids, helices and rods. The formation of such molecular communities through the collective behavior of molecules is not fully understood at a molecular level. All these self-assembled nanostructured materials have a wide range of applications such as drug delivery, gene delivery, biosensing, bioimaging, catalysis, tissue engineering, nano-electronics and sensing. Self-assembly is one of the most efficient and a simple strategy to generate complex functional materials. Owing to its significance, the last few decades witnessed a remarkable advancement in the field of self-assembling peptides with a plethora of new designer synthetic systems being discovered. These systems range from amphiphilic, cyclic, linear and polymeric peptides. This article presents only selected examples of such self-assembling peptides and pseudopeptides.

Ratiometric Recognition of Protons by a Multiple Tagged Designer Fluorescent Chemosensor.

Molecular architecture with different fluorophoric units can offer improved and effective recognition of biologically important analytes. We present here a new strategy for the design of ratiometric chemosensors that operate by photoinduced electron transfer (PET). This ratiometric sensor endowed with tryptophan and anthracene exhibits high sensitivity, excellent selectivity and remarkable reversibility towards recognition of H+ in methanol. This "Turn-On" type behaviour is crafted into the molecule by incorporation of bispidine entity. Effective quenching of the fluorescence of the anthracene by the adjacent amine groups of the bispidine results in negligible fluorescence from the anthracene group leading to highly sensitive recognition of protons by the compound as H+ protonate the amine functionalities giving rise to the emergence of the fluorescence from the anthracene group. This, combined with the reduction in the fluorescence from the Trp group by H+, results in highly sensitive ratiometric nature of the response especially at low [H+].

Designer Peptide-PVDF Composite Films for High-Performance Energy Harvesting.

Polymers and peptides have recently been considered as promising materials for piezoelectric energy harvesting because of their biocompatibility and enormous design possibility. However, achieving significant output voltages while meeting environmental safety requirements, low cost, and easy fabrication remains a major challenge. Herein, lipidated pseudopeptide incorporated poly(vinylidene fluoride) (PVDF) composite films are fabricated. Adding lipidated pseudopeptide (BLHA) increases the electroactive phase content, reaching the maximum for the 2 wt% composite film. The composite film containing 2 wt% BLHA manifests the highest dielectric constant and remnant polarization (Pr ), among others. A piezoelectric energy harvesting device fabricated with this film generates open-circuit output voltages up to 23 V, five times amplified output compared to pure PVDF. To the best of our knowledge, this material is superior among the peptide-based piezoelectric energy harvesters reported in the literature. The device is flexible, durable, low cost, and sensitive to high and low pressures. It can power up multiple liquid crystal display panels when pressed with a finger. The non-covalent interaction between BLHA and PVDF is the reason behind the composites' improved piezoelectric response. Density functional theory calculations also support this notion.

Hydrophobicity Directed Chiral Self-Assembly and Aggregation-Induced Emission: Diacetylene-Cored Pseudopeptide Chiral Dopants.

Here we delineate simple and tunable hydrophobically driven chiral functional assemblies of diacetylene cored pseudopeptides. These amino acid appended, rigid core dialkynes constitute promising chiral supramolecular building blocks for materials properties engineering. The chiral appended amino acid elements allow for simple tuning of solubility and interaction properties as well as governing chirality, while the central dialkyne core can impart hydrophobically driven assembly and Aggregation Induced Emission (AIE) properties. The self-assembly of these rod-like dialkynes can be regulated by tuning the solvent environment, with for example self-assembly into vesicles in acetonitrile and into helical organization with AIE in a H2 O/DMSO mixture. Of additional high interest, these supramolecular materials, themselves devoid of liquid crystal (LC) properties, can induce chirality into non-chiral LC matrices with high helical twisting power.

Designer Peptide and Protein Dendrimers: A Cross-Sectional Analysis.

Dendrimers have attracted immense interest in science and technology due to their unique chemical structure that offers a myriad of opportunities for researchers. Dendritic design allows us to present peptides in a branched three-dimensional fashion that eventually leads to a globular shape, thus mimicking globular proteins. Peptide dendrimers, unlike other classes of dendrimers, have immense applications in biomedical research due to their biological origin. The diversity of potential building blocks and innumerable possibilities for design, along with the fact that the area is relatively underexplored, make peptide dendrimers sought-after candidates for various applications. This review summarizes the stepwise evolution of peptidic dendrimers along with their multifaceted applications in various fields. Further, the introduction of biomacromolecules such as proteins to a dendritic scaffold, resulting in complex macromolecules with discrete molecular weights, is an altogether new addition to the area of organic chemistry. The synthesis of highly complex and fully folded biomacromolecules on a dendritic scaffold requires expertise in synthetic organic chemistry and biology. Presently, there are only a handful of examples of protein dendrimers; we believe that these limited examples will fuel further research in this area.

Effect of ionic liquid on the fluorescence of an intramolecular exciplex forming probe.

The effects of ionic liquid addition on the spectroscopic properties of a pyrene-tryptophan-containing fluorescent intramolecular complex in polar-aprotic and polar-protic solvents, specifically, acetonitrile and ethanol, are assessed. Two ionic liquid sets, consisting of seven different ionic liquids, were explored; set 1 comprised three imidazolium-containing ionic liquids paired with different anions while set 2 consisted of varying cations, namely, imidazolium, pyrrolidinium, ammonium, and pyridinium, partnered with a common anion, bis(trifluoromethylsulfonyl)imide ([Tf2N-]). The results provided herein reveal that all ionic liquids explored behave as quenchers, however, the imidazolium-, pyrrolidinium-, and ammonium-containing ionic liquids selectively quenched the fluorescence from the exciplex while the monomer emission from pyrene was largely unaffected relative to exciplex emission. Conversely, the pyridinium ionic liquid, significantly quenched the fluorescence from both the pyrene monomer and the pyrene-tryptophan exciplex, as was expected. The observed quenching is demonstrated to originate from the cations of the ionic liquids and is, in general, more efficient for an imidazolium ionic liquid that contains an acidic proton in the C2 position. Stern-Volmer plots of the exciplex quenching demonstrate a complex quenching mechanism that does not appear to follow any conventional quenching models with the data best fit to an exponential equation. Furthermore, time-resolved fluorescence measurements reveal that the quenching is not dynamic in nature as the recovered decay times do not systematically decrease with increasing ionic liquid concentration, suggesting a possible static quenching mechanism. Thus, the formation of a "dark" ensemble is proposed, in which the ionic liquid cations complex with or crowd around the exciplex, quenching the intramolecular energy transfer.

Redox Sensitive Self-Assembling Dipeptide for Sustained Intracellular Drug Delivery.

The rational design and synthesis of molecules with functional supramolecular assemblies continues to be a challenging endeavor. Self-assembled nano- and microstructures from natural building blocks are considered more appropriate for medical applications due to their biocompatible nature. We report for the first time a simple redox-responsive dipeptide that self-assembles to form vesicles in aqueous medium. The experimental results based on the control compound and all-atom molecular dynamics (MD) simulations support the mechanism of association through intermolecular π-π interactions between the indole rings of tryptophan residues. These peptide vesicles showed a DOX loading capacity of ∼16% (w/w) and redox-triggered controlled release of the packaged drug. The drug-loaded vesicles were able to penetrate into MDA-MB-231 and HeLa cells, and release payload, suggesting their putative use as chemotherapeutic delivery vehicles. These natural peptide-based carriers disassemble inside cells due to the high cytosolic GSH concentration, and the resultant Cys-Trp dipeptide is degradable. The minimalistic peptide design presented here, coupled with the propensity to form vesicles that can encapsulate the chemotherapeutic drug, opens up unlimited potential for engineering targeted sustained-release drug delivery vehicles.

Self-assembling polymeric dendritic peptide as functional osteogenic matrix for periodontal regeneration scaffolds-an in vitro study.

OBJECTIVE: Regeneration of periodontal defects is challenging as it necessitates the formation of complex tissue structure with cementum, periodontal ligament, and alveolar bone. Rather than the conventional barrier membranes, scaffolds mimicking extracellular matrix (ECM) can achieve faster healing as they promote migration, adhesion, and differentiation of native progenitor cells. This work explores the possibility of a functional osteogenic matrix based on self-assembling peptide appended dendritic polydiacetylene in regenerating diseased periodontia. METHOD: The amino acid lysine was appended onto a diacetylene core, which was converted to a polymeric dendritic lysine matrix (Lys-PDA) through photopolymerization. This bioactive matrix was evaluated in vitro for the viability, adhesion, spreading, and differentiation of cultured human periodontal ligament (hPDL) progenitor cells. Its osteogenic differentiation was analysed by histologic staining and expression of osteogenic markers (alkaline phosphatase and Osteonectin). Electrospun polycaprolactone (PCL) mat, a candidate barrier material, was fabricated and functionalized with Lys-PDA matrix, and the cell viability, adhesion, and spreading of hPDL cells were evaluated. RESULTS: The dendritic Lys-PDA matrix well supported the hPDL cell growth and differentiation. The cells were viable and showed good cytoskeletal organization. Early expression of osteogenic markers and mineralization was noted in vitro in the presence of Lys-PDA matrix. The electrospun PCL mat functionalized with Lys-PDA maintained the viability, morphology, and spreading of the hPDL cells. SIGNIFICANCE: The ECM mimetic dendritic peptide matrices are capable of hosting and differentiating cells which can lead to the regeneration of periodontal tissue architecture. They could be used in conjunction with barrier membranes for better results.

Comparative Assessment of Active Targeted Redox Sensitive Polymersomes Based on pPEGMA-S-S-PLA Diblock Copolymer with Marketed Nanoformulation.

In the present work, polymersomes based on self-assembled, folate-targeted, redox-responsive, ATRP-based amphiphilic diblock copolymer poly(polyethylene glycol)-S-S-polylactide with disulfide linkage were developed for efficient doxorubicin (DOX) delivery and compared with marketed DOXIL nanoformulation. The polymersomes formulation was optimized by quality by design approach providing monodisperse nanostructures of ∼110 nm and enhanced DOX loading of ∼20%. Polymersomes showed excellent stability as per the ICH guidelines over the extended storage period of 3 months. The in vitro drug release profile confirmed the redox sensitive behavior of polymersomes providing ∼80% drug release in endosomal pH 5 with 10 mmol GSH as compared to ∼20% release at pH 7.4. The targeted polymersomes achieved enhanced cellular internalization in folate receptor overexpressing cell lines, MDA-MB-231 and HeLa, providing ∼24% higher tumor reduction than DOXIL in Ehrlich ascites tumor bearing Swiss albino mice.

Modulation of prion polymerization and toxicity by rationally designed peptidomimetics.

Misfolding and aggregation of cellular prion protein is associated with a large array of neurological disorders commonly called the transmissible spongiform encephalopathies. Designing inhibitors against prions has remained a daunting task owing to limited information about mechanism(s) of their pathogenic self-assembly. Here, we explore the anti-prion properties of a combinatorial library of bispidine-based peptidomimetics (BPMs) that conjugate amino acids with hydrophobic and aromatic side chains. Keeping the bispidine unit unaltered, a series of structurally diverse BPMs were synthesized and tested for their prion-modulating properties. Administration of Leu- and Trp-BPMs delayed and completely inhibited the amyloidogenic conversion of human prion protein (HuPrP), respectively. We found that each BPM induced the HuPrP to form unique oligomeric nanostructures differing in their biophysical properties, cellular toxicities and response to conformation-specific antibodies. While Leu-BPMs were found to stabilize the oligomers, Trp-BPMs effected transient oligomerization, resulting in the formation of non-toxic, non-fibrillar aggregates. Yet another aromatic residue, Phe, however, accelerated the aggregation process in HuPrP. Molecular insights obtained through MD (molecular dynamics) simulations suggested that each BPM differently engages a conserved Tyr 169 residue at the α2-ß2 loop of HuPrP and affects the stability of α2 and α3 helices. Our results demonstrate that this new class of molecules having chemical scaffolds conjugating hydrophobic/aromatic residues could effectively modulate prion aggregation and toxicity.