02399nas a2200217   4500008004100000022001400041245011200055210006900167260000800236300001200244490000700256520161500263653001301878653003401891653003101925653002401956653003301980100002302013700001502036856013002051       2023                        eng d  a0887-358500aGoverning dynamics and preferential binding of the AXH domain influence the aggregation pathway of Ataxin-10 aGoverning dynamics and preferential binding of the AXH domain in  cMAR  a380-3940 v913 a<p>
	The present state of understanding the mechanism of Spinocerebellar Ataxia-1, a fatal neurodegenerative disease linked to the protein Ataxin-1 (ATXN1), is baffled by a set of self-contradictory, and hence, inconclusive observations. This fallacy poses a bottleneck to the effective designing of curable drugs as the field is currently missing the specific druggable site. To understand the fundamentals of pathogenesis, we tried to decipher the intricacies of the extremely complicated landscape by targeting the relevant species that supposedly dictate the structure-function paradigm. The atomic-level description and characterization of the dynamism of the systems reveal the existence of structural polymorphism in all the leading stakeholders of the overall system. The very existence of conformational heterogeneity in every species creates numerous possible combinations of favorable interactions because of the variability in segmental cross-talks and hence claims its role in the choice of routes between functional activity and dysfunctional disease-causing aggregation. Despite this emergent configurational diversity, there is a common mode of operative intermolecular forces that dictates the extent of stability of all the multimeric complexes due to the localized population of a specific type of residue. The present research proposes a dynamic switch mechanism between aggregability and functional activity, based on the logical interpretation of the estimated variables, which is practically dictated by the effective concentration of the interacting species involved in the cell.</p>
10aAtaxin-110amolecular dynamics simulation10aneurodegenerative diseases10aProtein aggregation10aprotein misfolding disorders1 aTammara, Vaishnavi1 aDas, Atanu  uhttp://library.ncl.res.in/content/governing-dynamics-and-preferential-binding-axh-domain-influence-aggregation-pathway-ataxin02449nas a2200157   4500008004100000022001400041245005700055210005600112260000800168300001400176490000800190520197000198100002302168700001502191856008502206       2023                        eng d  a1520-610600aMolecular mechanism of PSMa3 aggregation: a new view0 aMolecular mechanism of PSMa3 aggregation a new view  cSEP  a8317-83300 v1273 a<p>
	The emergence of a novel cross-alpha fibrillar structure, unlike the commonly observed sequence-independent cross-beta one, of a 22-residue bacterial virulent amphipathic alpha-helical peptide of the phenol soluble modulin (PSM) family, PSM alpha 3, with many deleterious effects on human life, has infused uncertainty to the paradigm of the intrinsically polymorphic, multivariate, multiphasic, and cross-sequence-cross-disease entangled protein aggregation landscape and hence on the identity of the therapeutic target. We, here, deconvolute the factors contributing to the genesis and hence the transition of lower to higher order aggregates of PSM alpha 3 in its natural state and three noncanonical designed variants using conventional and enhanced sampling approach-based atomistic simulations. PSM alpha 3 shows structural polymorphism with nominal alpha-helicity, substantial beta-propensity, and dominant random-coil features, irrespective of the extent of aggregation. Moreover, the individual features of the overall amphipathicity operate alternatively depending on the extent and organization of aggregation; the dominance gradually moves from charged to hydrophobic residues with the progressive generation of higher order aggregates (dimer to oligomer to fibril) and with increasing orderedness of the self-assembled construct (oligomer vs dimer/fibril). Similarly, the contribution of interchain salt bridges decreases with increasing order of aggregation (dimer to oligomer to fibril). However, the intrachain salt bridges consistently display their role in all phases of aggregation. Such phase-independent features also include equivalent roles of electrostatic and van der Waals forces on intrachain interactions, sole contribution of van der Waals forces on interchain cross-talk, and negligible peptide-water relationship. Finally, we propose a conjugate peptide-based aggregation suppressor having a single-point proline mutation.</p>
1 aTammara, Vaishnavi1 aDas, Atanu  uhttp://library.ncl.res.in/content/molecular-mechanism-psma3-aggregation-new-view