Electronic absorption spectra of proteins are primarily characterized over the ultraviolet region (185–320 nm) of the electromagnetic spectrum. While recent studies on peptide aggregates have revealed absorption beyond 350 nm, monomeric proteins lacking aromatic amino acids, disulphide bonds, and active site prosthetic groups are expected to remain optically silent beyond 250 nm. Here, in a joint theoretical and experimental investigation, we report the distinctive UV-Vis absorption spectrum between 250 nm [ε = 7338 M⁻¹ cm⁻¹] and 800 nm [ε = 501 M⁻¹ cm⁻¹] in a synthetic 67 residue protein (α₃C), in monomeric form, devoid of aromatic amino acids. Systematic control studies with high concentration non-aromatic amino acid solutions revealed significant absorption beyond 250 nm for charged amino acids which constitute over 50% of the sequence composition in α₃C. Classical atomistic molecular dynamics (MD) simulations of α₃C reveal dynamic interactions between multiple charged sidechains of Lys and Glu residues present in α₃C. Time-dependent density functional theory calculations on charged amino acid residues sampled from the MD trajectories of α₃C reveal that the distinctive absorption features of α₃C may arise from two different types of charge transfer (CT) transitions involving spatially proximal Lys/Glu amino acids. Specifically, we show that the charged amino (NH₃ ⁺)/carboxylate (COO⁻) groups of Lys/Glu sidechains act as electronic charge acceptors/donors for photoinduced electron transfer either from/to the polypeptide backbone or to each other. Further, the sensitivity of the CT spectra to close/far/intermediate range of encounters between sidechains of Lys/Glu owing to the three dimensional protein fold can create the long tail in the α₃C absorption profile between 300 and 800 nm. Finally, we experimentally demonstrate the sensitivity of α₃C absorption spectrum to temperature and pH-induced changes in protein structure. Taken together, our investigation significantly expands the pool of spectroscopically active biomolecular chromophores and adds an optical 250–800 nm spectral window, which we term ProCharTS (Protein Charge Transfer Spectra), for label free probes of biomolecular structure and dynamics.

Recent studies have shown that high coverages of alkyl groups can be generated and isolated on metal surfaces under ultrahigh vacuum conditions by the thermal [Zaera, F., Acc. Chem. Res. 25, 260 (1992)] and photochemical [Zhou, X. -L., Zhu, X. -Y., and White, J. M., Surf. Sci. Rep. 13, 74 (1991)] dissociation of alkyl halides. This paper describes studies in which these approaches have been employed to study the coupling of methyl groups generated on a Au(111) surface. The coupling rate, as measured by temperature-programmed reaction experiments, is found to be sensitive to the structure of the surface. For a well-annealed surface, coupling occurs at ∼ 270 K, but for a sputtered and incompletely annealed surface, coupling occurs at ∼ 350 K. An interesting and unexpected finding is that coadsorbing P(CH₃)₃ with the methyl groups on a Au(100) surface inhibits the coupling reaction so that methyl radical desorption is observed. Similarities between the rates of methyl coupling and methyl radical desorption have also been observed previously for a Cu(111) surface, suggesting a correlation between the methyl coupling rate and the metal-alkyl bond strength. Such a correlation can account for the trends in the coupling rates reported for alkyl groups on Ag(111), Au(100), Cu(111), and Cu(110). The coupling rate is fastest on surfaces and for alkyl groups that are expected to form the weakest carbon-metal bonds.

A novel class of anthranilic acid containing a conformationally restricted β-sheet breaker α/β-hybrid peptide efficiently disrupts preformed fibrillar aggregates of Aβ_1–40in vitro.

Intra-cellular tau protein tangles and extra-cellular β-amyloid plaques are hallmarks of Alzheimer’s disease (AD), characterized by the conversion of natively unfolded monomeric protein/peptide into misfolded β-sheet rich aggregates. Therefore, inhibiting the aggregation cascade or disassembling the pre-formed aggregates becomes a pivotal event in disease treatment. In the present study, we show that Naphthoquinone-Tryptophan hybrids, i.e., NQTrp and Cl-NQTrp significantly disrupted the pre-formed fibrillar aggregates of Tau-derived PHF6 (VQIVYK) peptide and full-length tau proteinin vitro, in a dose-dependent manner as evident from ThS assay, CD spectroscopy, and TEM. Molecular dynamics simulation of PHF6 oligomers and fibrils with the Naphthoquinone-Tryptophan hybrids provides a possible structure-function based mechanism-of-action, highlighting the role of hydrophobic interaction and hydrogen bond formation during fibril disassembly. These findings signify the effectiveness of NQTrp and Cl-NQTrp in disassembling fibrillar aggregates and may help in designing novel hybrid molecules for AD treatment.

Protein misfolding and aggregation have been associated with several human disorders, including Alzheimer’s, Parkinson’s and Huntington’s diseases, as well as senile systemic amyloidosis and Type II diabetes. However, there is no current disease-modifying therapy available for the treatment of these disorders. In spite of extensive academic, pharmaceutical, medicinal and clinical research, a complete mechanistic model for this family of diseases is still lacking. In this review, we primarily discuss the different types of small molecular entities which have been used for the inhibition of the aggregation process of different amyloidogenic proteins under diseased conditions. These include small peptides, polyphenols, inositols, quinones and their derivatives, and metal chelator molecules. In recent years, these groups of molecules have been extensively studied using in vitro, in vivo and computational models to understand their mechanism of action and common structural features underlying the process of in...

The aggregation of the amyloidogenic protein α-synuclein (α-Syn) into toxic oligomers and mature fibrils is the major pathological hallmark of Parkinson's disease (PD). Small molecules that inhibit α-Syn aggregation thus may be useful therapeutics for PD. Mannitol and naphthoquinone-tryptophan (NQTrp) have been shown in the past to inhibit α-Syn aggregation by different mechanisms. Herein, we tested whether the conjugation of Mannitol and NQTrp may result in enhance efficacy toward α-Syn. The molecules were conjugated either by a click linker or via a PEG linker. The effect of the conjugate molecules on α-Syn aggregation in vitro was monitored using Thioflavin T fluorescence assay, circular dichroism, transmission electron microscopy, and Congo red birefringence assay. One of the conjugate molecules was found to be more effective than the two parent molecules and as effective as a mixture of the two. The conjugate molecules attenuated the disruptive effect of α-Syn on artificial membrane of Large Unilamellar Vesicles as monitored by dye leakage assay. The conjugates were found to be have low cytotoxicity and reduced toxicity of α-Syn toward SH-SY5Y neuroblastoma cells. These novel designed entities can be attractive scaffold for the development of therapeutic agents for PD.