@article {47662,
	title = {Systematic search for a predictor for the clinical observables of alzheimer{\textquoteright}s disease},
	journal = {Journal of Physical Chemistry B},
	volume = {125},
	year = {2021},
	month = {NOV },
	pages = {12177-12186},
	type = {Article},
	abstract = {One of the prevailing life-threatening incurable neurodegenerative diseases that are presently endangering human society as a whole, and hence, baffling the entire spectrum of the scientific and pharmaceutical world, is Alzheimer{\textquoteright}s disease (AD). AD is a manifestation of self-assembly of both wild-type (sporadic) and mutated (familial) forms of the amyloid-beta peptide, a proteolytic product of the amyloid precursor protein, where the self-assembly results in the genesis of pathogenic fibrillar aggregates. Currently prevailing diagnostic and hence therapeutic challenges originate from the unavailability of a specific predictor for clinical observables. The continuous emergence of novel pathogenic mutants with unpredictable phenotypes adds immensely to the nonspecific nature of the problem. The current research reports a simple physical parameter, the binding affinity of a protofilament to its protofibril, which predicts the clinical observables of familial AD with astounding accuracy and more importantly, without any adjustable parameters.},
	issn = {1520-6106},
	doi = {10.1021/acs.jpcb.1c06725},
	author = {Das, Atanu}
}
@article {48219,
	title = {Scan-find-scan-model: discrete site-targeted suppressor design strategy for amyloid-beta},
	journal = {ACS Chemical Neuroscience},
	volume = {13},
	year = {2022},
	month = {JUL},
	pages = {2191-2208},
	type = {Article},
	abstract = {<p>
	Alzheimer{\textquoteright}s disease is undoubtedly the most well-studied ranks at the top in terms of getting attention from the scientific community for structural property-based characterization. Even after decades of extensive research, there is existing volatility in terms of understanding and hence the effective tackling procedures against the disease that arises due to the lack of knowledge of both specific targetand site-specific drugs. Here, we develop a multidimensional approach based on the characterization of the common static-dynamic-thermodynamic trait of the monomeric protein, which efficiently identifies a small target sequence that contains an inherent tendency to misfold and consequently aggregate. The robustness of the identification of the target sequence comes with an abundance of a priori knowledge about the length and sequence of the target and hence guides toward effective designing of the target-specific drug with a very low probability of bottleneck and failure. Based on the target sequence information, we further identified a specific mutant that showed the maximum potential to act as a destabilizer of the monomeric protein as well as enormous success as an aggregation suppressor. We eventually tested the drug efficacy by estimating the extent of modulation of binding affinity existing within the fibrillar form of the A beta protein due to a single-point mutation and hence provided a proof of concept of the entire protocol.</p>
},
	keywords = {configurational misfoldability, drug developability, inherent frustration, potential aggregability, sequence-based mutability, target specificity},
	issn = {1948-7193},
	doi = {10.1021/acschemneuro.2c00272},
	author = {Bhagavatula, Hasathi and Sarkar, Archishman and Santra, Binit and Das, Atanu}
}
@article {49188,
	title = {Self-consistent molecular mechanism of β2-microglobulin aggregation},
	journal = {Journal of Physical Chemistry B},
	volume = {128},
	year = {2024},
	month = {DEC},
	pages = {12425-12442},
	type = {Article},
	abstract = {<p>
	Despite the consensus on the origin of dialysis-related amyloidosis (DRA) being beta(2)-microglobulin (beta(2)m) aggregation, the debate on the underlying mechanism persists because of the continuous emergence of beta(2)m variant- and pH-dependent contradictory results. By characterizing the native monomeric (initiation) and aggregated fibrillar (termination) states of beta(2)m via a combination of two enhanced sampling approaches, we here propose a mechanism that explains the heterogeneous behavior of wild-type (WT) and pathogenic (V27M and D76N) beta(2)m variants in physiological and disease-pertinent acidic pH environments. It appears that the higher retainment of monomeric native folds at neutral pH (native-like) distinguishes pathogenic beta(2)m mutants from the WT (moderate loss). However, at acidic pH, all three variants behave similarly in producing a substantial amount of partially unfolded states (conformational switch, propensity), though with different extents (WT \&lt; V27M \&lt; D76N). Whereas at the fibrillar end, all beta(2)m variants display a pH-dependent protofilament separation pathway and a higher protofilament binding affinity (stability) at acidic pH, where the relative order of binding affinity (WT \&lt; V27M \&lt; D76N) remains consistent with pH modulation. Combining these observations, we conclude that beta(2)m variants possibly shift from native-like aggregation to conformational switch-initiated fibrillation as the pH is altered from neutral to acidic. The combined propensity-stability approach based on the initiation and termination points of beta(2)m aggregation not only assists us in deciphering the mechanism but also emphasizes the protagonistic roles of both terminal points in the overall aggregation process.</p>
},
	issn = {1520-6106},
	doi = {10.1021/acs.jpcb.4c06611},
	author = {Tammara, Vaishnavi and Das, Atanu}
}
