01573nas a2200145   4500008004100000022001400041245009000055210006900145260000900214300001600223490000800239520105900247100001501306856010601321       2021                        eng d  a1520-610600aSystematic search for a predictor for the clinical observables of alzheimer's disease0 aSystematic search for a predictor for the clinical observables o  cNOV   a12177-121860 v1253 aOne 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'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.1 aDas, Atanu  uhttp://library.ncl.res.in/content/systematic-search-predictor-clinical-observables-alzheimers-disease02342nas a2200253   4500008004100000022001400041245009300055210006900148260000800217300001400225490000700239520147400246653003501720653002401755653002501779653002801804653003001832653002301862100002501885700002301910700001801933700001501951856012201966       2022                        eng d  a1948-719300aScan-find-scan-model: discrete site-targeted suppressor design strategy for amyloid-beta0 aScanfindscanmodel discrete sitetargeted suppressor design strate  cJUL  a2191-22080 v133 a<p>
	Alzheimer'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>
10aconfigurational misfoldability10adrug developability10ainherent frustration10apotential aggregability10asequence-based mutability10atarget specificity1 aBhagavatula, Hasathi1 aSarkar, Archishman1 aSantra, Binit1 aDas, Atanu  uhttp://library.ncl.res.in/content/scan-find-scan-model-discrete-site-targeted-suppressor-design-strategy-amyloid-beta02319nas a2200157   4500008004100000022001400041245007300055210007000128260000800198300001600206490000800222520178500230100002302015700001502038856010802053       2024                        eng d  a1520-610600aSelf-consistent molecular mechanism of β2-microglobulin aggregation0 aSelfconsistent molecular mechanism of β2microglobulin aggregatio  cDEC  a12425-124420 v1283 a<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>
1 aTammara, Vaishnavi1 aDas, Atanu  uhttp://library.ncl.res.in/content/self-consistent-molecular-mechanism-%CE%B22-microglobulin-aggregation