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    • More recently Dal Peraro and coworkers carried out s

    2022-06-17

    More recently, Dal Peraro and coworkers [38] carried out 4 μs CG MD simulations of GS with six randomly placed C9915-55 peptides embedded into a synaptic plasma bilayer model. This lipid raft model was constituted by 32 different Darunavir Ethanolate and cholesterol (54.74%). In this study, the authors observed a high interaction preference of C99 N-terminal region for the NCT ECD. The latter suggested that C99 is initially identified by NCT ECD to subsequently be translocated to PS1 active site. In addition, their simulations showed that localization of C9915-55 in the bilayer model is dependent on the cholesterol concentration, suggesting that cholesterol may play a critical role in substrate recognition and recruitment [39].
    Characterizing the active and inactive GS states A general overview of six GS cryo-EM structures deposited in the PDB shows that the main difference between them is due to the large conformational variations of the PS1 component (Fig. 1d). The tilt analysis of the nine PS1 TMs helices indicates the wide variety of PS1 conformers, being TM6 the one with the highest tilt angle distribution range (Fig. 1e). Interestingly, TM6 tilt angle variations are directly related with the measured distances between the catalytic aspartate residues (Fig. 1f). Structures with Darunavir Ethanolate a TM6 tilt angle values smaller than 20° have smaller distances (≤6.0 Å), while the structures (i.e. 5A63 and 5FN4) with larger TM6 tilt angles have larger Asp250-Asp385 distances. Since a small distance between the catalytic Asp residues is required to carry out the catalysis, these distance has been directly associated with the active state of aspartyl proteases [23]. Recently, our research group performed a multiscale MD study combining atomistic (1 μs) and CG (50 replicas of 1 μs) GS models embedded into a POPC bilayer to describe two possible PS1 activation states based on the above-mentioned order parameters (catalytic Asp distance and TMs tilt angles) [40]. Importantly, the transition from the inactive (state 1) to the active (state 2) conformations showed to be dependent on the protonation state of the catalytic aspartates. Inactive conformers were predominant in systems with unprotonated catalytic aspartics, while protonated systems displayed PS1 conformers in the active state (Fig. 1g). Our atomistic MD simulations allowed us to characterize interactions of PS1 with the rest of the complex and identify key interactions between catalytic aspartics and water molecules located in the active state (Fig. 1h). Interestingly, correlated motions between TM2 and TM6 obtained from the CG simulations agree with observations from the previous atomistic isolated PS1 model and the complete GS simulation models performed by Somavarapu and Kepp [29,36]. Furthermore, our multiscale model approach allowed us to identify the dynamic conformational ensemble of NCT ECD, in agreement with experimental information reported by Chávez-Gutierrez [41] and coworkers. The latest GS MD simulation study was published by Bahar's group [42], in which they examined the GS dynamics using an anisotropic network model (ANM) [43,44] and a CG MD simulation model to elucidate its intrinsically favored collective motions. Interestingly, their ANM study revealed bending (up-down motion) and twisting (left-right rotation) as the principal movements of NCT ECD, which agrees with our previous CG MD study. Interestingly, the authors explained that the “open” and “closed” conformational states could alter the access of substrate to the active site. The ANM study also showed an asymmetric breathing motion during the reconfiguration of PS1, leading to the formation of compact and stretched states. Remarkably, this PS1 reconfiguration agrees with semiopen and open PS1 conformations reported by Somavarapu and Kepp [36] (see Fig. 1c) and corroborate their possible significance during the Aβ production (see the previous section). They also identified a mechanism that couples the NCT ligand-biding and the PS1 catalytic site that could play a key role during the substrate recruitment and positioning for cleavage. Their druggability simulations showed that regions with correlation events could act as potential orthosteric and allosteric binding sites for the inhibition/modulation of the catalytic activity. And finally, their molecular docking study showed a high preference of GS inhibitors (GSIs) for an orthosteric binding site (R1: M146, T147, W165 and M233), whereas a high affinity of an allosteric site (R2: Y106, Y115, N135, F177 and Y24) was observed for two GS modulators (GSMs). These results are consistent with previous experimental data, confirming that GSMs alter PS1 conformations affecting the GS trimming activity and the substrate recognition mechanisms [[45], [46], [47], [48], [49], [50]].