<?xml version="1.0" encoding="UTF-8"?><xml><records><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Tammara, Vaishnavi</style></author><author><style face="normal" font="default" size="100%">Doke, Abhilasha A.</style></author><author><style face="normal" font="default" size="100%">Jha, Santosh Kumar</style></author><author><style face="normal" font="default" size="100%">Das, Atanu</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Deciphering the monomeric and dimeric conformational landscapes of the full-length TDP-43 and the impact of the C-terminal domain</style></title><secondary-title><style face="normal" font="default" size="100%">ACS Chemical Neuroscience</style></secondary-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">chain collapsibility</style></keyword><keyword><style  face="normal" font="default" size="100%">domain-wisefluctuation</style></keyword><keyword><style  face="normal" font="default" size="100%">electrostatic dominance</style></keyword><keyword><style  face="normal" font="default" size="100%">hydrogen bond switchability</style></keyword><keyword><style  face="normal" font="default" size="100%">long-range crosstalk</style></keyword><keyword><style  face="normal" font="default" size="100%">persistent beta-character</style></keyword><keyword><style  face="normal" font="default" size="100%">protagonistic C-terminal domain</style></keyword><keyword><style  face="normal" font="default" size="100%">rugged phase space</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2024</style></year><pub-dates><date><style  face="normal" font="default" size="100%">NOV</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">15</style></volume><pages><style face="normal" font="default" size="100%">4305-4321</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;
	The aberrant aggregation of TAR DNA-binding protein 43 kDa (TDP-43) in cells leads to the pathogenesis of multiple fatal neurodegenerative diseases. Decoding the proposed initial transition between its functional dimeric and aggregation-prone monomeric states can potentially design a viable therapeutic strategy, which is presently limited by the lack of structural detail of the full-length TDP-43. To achieve a complete understanding of such a delicate phase space, we employed a multiscale simulation approach that unearths numerous crucial features, broadly summarized in two categories: (1) state-independent features that involve inherent chain collapsibility, rugged polymorphic landscape dictated by the terminal domains, high beta-sheet propensity, structural integrity preserved by backbone-based intrachain hydrogen bonds and electrostatic forces, the prominence of the C-terminal domain in the intrachain cross-domain interfaces, and equal participation of hydrophobic and hydrophilic (charged and polar) residues in cross-domain interfaces; and (2) dimerization-modulated characteristics that encompass slower collapsing dynamics, restricted polymorphic landscape, the dominance of side chains in interchain hydrogen bonds, the appearance of the N-terminal domain in the dimer interface, and the prominence of hydrophilic (specifically polar) residues in interchain homo- and cross-domain interfaces. In our work, the ill-known C-terminal domain appears as the most crucial structure-dictating domain, which preferably populates a compact conformation with a high beta-sheet propensity in its isolated state stabilized by intrabackbone hydrogen bonds, and these signatures are comparatively faded in its integrated form. Validation of our simulated observables by a complementary spectroscopic approach on multiple counts ensures the robustness of the computationally predicted features of the TDP-43 aggregation landscape.&lt;/p&gt;
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