@article {48447, title = {Governing dynamics and preferential binding of the AXH domain influence the aggregation pathway of Ataxin-1}, journal = {Proteins-Structure Function and Bioinformatics}, volume = {91}, year = {2023}, month = {MAR}, pages = {380-394}, type = {Article}, abstract = {

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.

}, keywords = {Ataxin-1, molecular dynamics simulation, neurodegenerative diseases, Protein aggregation, protein misfolding disorders}, issn = {0887-3585}, doi = {10.1002/prot.26436}, author = {Tammara, Vaishnavi and Das, Atanu} } @article {48711, title = {Molecular mechanism of PSMa3 aggregation: a new view}, journal = {Journal of Physical Chemistry B}, volume = {127}, year = {2023}, month = {SEP}, pages = {8317-8330}, type = {Article}, abstract = {

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.

}, issn = {1520-6106}, doi = {10.1021/acs.jpcb.3c03806}, author = {Tammara, Vaishnavi and Das, Atanu} } @article {48981, title = {Flagellar motor protein-targeted search for the druggable site of Helicobacter pylori}, journal = {Physical Chemistry Chemical Physics }, volume = {26}, year = {2024}, month = {JAN }, pages = {2111-2126}, type = {Article}, abstract = {

The deleterious impact of Helicobacter pylori (H. pylori) on human health is contingent upon its ability to create and sustain colony structure, which in turn is dictated by the effective performance of flagella - a multi-protein rotary nanodevice. Hence, to design an effective therapeutic strategy against H. pylori, we here conducted a systematic search for an effective druggable site by focusing on the structure-dynamics-energetics-stability landscape of the junction points of three 1 : 1 protein complexes (FliF(C)-FliG(N), FliG(M)-FliM(M), and FliY(C)-FliN(C)) that contribute mainly to the rotary motion of the flagella via the transformation of information along the junctions over a wide range of pH values operative in the stomach (from neutral to acidic). We applied a gamut of physiologically relevant perturbations in the form of thermal scanning and mechanical force to sample the entire quasi - and non-equilibrium conformational spaces available for the protein complexes under neutral and acidic pH conditions. Our perturbation-induced magnification of conformational distortion approach identified pH-independent protein sequence-specific evolution of precise thermally labile segments, which dictate the specific thermal unfolding mechanism of each complex and this complex-specific pH-independent structural disruption notion remains consistent under mechanical stress as well. Complementing the above observations with the relative rank-ordering of estimated equilibrium binding free energies between two protein sequences of a specific complex quantifies the extent of structure-stability modulation due to pH alteration, rationalizes the exceptional stability of H. pylori under acidic pH conditions, and identifies the pH-independent complex-sequence-segment-residue diagram for targeted drug design.

}, issn = {1463-9076}, doi = {10.1039/d3cp05024f}, author = {Tammara, Vaishnavi and Angrover, Ruchika and Sirur, Disha and Das, Atanu} }