Biology subjects

Hassanali, A.

Publications and source records attributed to Hassanali, A..

4 recordsLinked to original sources

bioRxiv2022

Intracellular Aβ42 aggregation leads to cellular thermogenesis

The aggregation of A{beta}42 is a hallmark of Alzheimers disease. It is still not known what the biochemical changes are inside a cell which will eventually lead to A{beta}42 aggregation. Thermogenesis has been associated with cellular stress, the latter of which may promote aggregation. We perform intracellular thermometry measurements using fluorescent polymeric thermometers (FPTs) to show that A{beta}42 aggregation in live cells leads to an increase in cell-averaged temperatures. This rise in temperature is mitigated upon treatment with an aggregation inhibitor of A{beta}42 and is independent of mitochondrial damage that can otherwise lead to thermogenesis. With this, we present a diagnostic assay which could be used to screen small-molecule inhibitors to amyloid proteins in physiologically relevant settings. To interpret our experimental observations and motivate the development of future models, we perform classical molecular dynamics of model A{beta} peptides to examine the factors that hinder thermal disspation. We observe that this is controlled by the presence of ions in its surrounding environment, the morphology of the amyloid peptides and the extent of its hydrogen-bonding interactions with water. We show that aggregation and heat retention by A{beta} peptides are favoured under intracellular-mimicking ionic conditions, which could potentially promote thermogenesis. The latter will, in turn, trigger further nucleation events that accelerate disease progression.

biophysics↗

bioRxiv2021

On-off transition and ultrafast decay of amino acid luminescence driven by modulation of supramolecular packing

It has been experimentally observed that various biomolecules exhibit clear luminescence in the visible upon aggregation, contrary their monomeric state. However, the physical basis for this phenomenon is still elusive. Here, we systematically examine all coded amino acids to provide non-biased insights into this phenomenon. Several amino acids, including non-aromatic, show intense visible luminescence. While lysine crystals display the highest signal, the very chemically similar non-coded ornithine does not, implying a role for molecular packing rather than the chemical characteristics of the molecule. Furthermore, cysteine show luminescence that is indeed crystal-packing-dependent as repeated rearrangements between two crystal structures result in a reversible on-off optical transition. In addition, ultrafast lifetime decay is experimentally validated, corroborating a recently raised hypothesis regarding the governing role of n{pi}* states in the emission formation. Collectively, our study supports the hypothesis that electronic interactions between molecules that are non-fluorescent and non-absorbing at the monomeric state may result in reversible optically-active states by the formation of supramolecular fluorophores.

biophysics↗

bioRxiv2020

Intrinsic fluorescence in non-aromatic peptide structures is induced by collective vibrations, charge reorganisation and short hydrogen bonds, as shown in a new glutamine-related structure

Fluorescence in biological systems is usually associated with the presence of aromatic groups. Here, we show that specific hydrogen bonding networks can significantly affect fluorescence employing a combined experimental and computational approach. In particular, we reveal that the single amino acid L-glutamine, by undergoing a chemical transformation leading to the formation of a short hydrogen bond, displays optical properties that are significantly enhanced compared to L-glutamine itself. Ab initio molecular dynamics simulations highlight that these short hydrogen bonds prevent the appearance of a conical intersection between the excited and the ground states and thereby significantly decrease non-radiative transition probabilities. Our findings open the doors for the design of new photoactive materials with biophotonic applications. Significance statementIntrinsic fluorescence of non-aromatic amino acids is a puzzling phenomenon with an enormous potential for technological and biomedical applications. The physical origins of this effect, however, remain elusive. Herein, we demonstrate how specific hydrogen bond networks can modulate fluorescence. We highlight the key role played by short hydrogen bonds in the networks on the ensuing fluorescence and we provide a detailed molecular mechanism to explain this unusual non-aromatic optical properties. Our findings should benefit the design of novel optically active biomaterials for applications in biosensing and imaging.

biophysics↗

bioRxiv2016

Hydrogen Bond Networks and HydrophobicEffects in the Amyloid β30-35 Chain in Water: A Molecular Dynamics Study

We study the conformational landscape of the C-terminal fragment of the Amyloid protein A{beta}30-35 in water using well-tempered metadynamics simulations and find that it resembles an intrinsically disordered protein. The conformational fluctuations of the protein are facilitated by a collective reorganization of both protein and water hydrogen bond networks, combined with electrostatic interactions between termini as well as hydrophobic interactions of the side chains. The stabilization of hydrophobic interactions in one of the conformers involves a collective collapse of the sidechains along with a squeeze out of water sandwiched in between. The charged N and C termini play a critical role in stabilizing different types of protein conformations including those involving contact ion salt-bridges as well as solvent mediated interactions of the termini and amide backbone. We examine this by probing the distribution of directed water wires forming the hydrogen bond network enveloping the polypeptide. Water wires and their fluctuations form an integral part of structural signature of the protein conformation.

neuroscience↗