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C99 is the immediate precursor for amyloid beta (Aβ) and therefore is a central intermediate in the pathway that is believed to result in Alzheimer’s disease (AD). It has been suggested that cholesterol is associated with C99, but the dynamic details of how cholesterol affects C99 assembly and the Aβ formation remain unclear. To investigate this question, we employed coarse-grained and all-atom molecular dynamics simulations to study the effect of cholesterol and membrane composition on C99 dimerization. We found that although the existence of cholesterol delays C99 dimerization, there is no direct competition between C99 dimerization and cholesterol association. In contrast, the existence of cholesterol makes the C99 dimer more stable, which presents a cholesterol binding C99 dimer model. Cholesterol and membrane composition change the dimerization rate and conformation distribution of C99, which will subsequently influence the production of Aβ. Our results provide insights into the potential influence of the physiological environment on the C99 dimerization, which will help us understand Aβ formation and AD’s etiology.

Incidents of breast cancer (BC) are on the rise on a daily basis and have proven to be the most prevelant cause of death for women in both developed and developing countries. Among total BC cases diagnosed after menopause, 70% of cases are Estrogen Receptor (ER) positive (ER-positive or ER+). Mutations in the LBD (ligand-binding domain) of the ER have recently been reported to be the major cause of resistance to potent antagonists. In this study, the experimentally reported mutations K303R, E380Q, V392I, S463P, V524E, P535H, P536H, Y537C, Y537N, Y537S, and D538G were analyzed, and the most significant mutations were shortlisted based on multiple analyses. Initial analyses, such as mCSM stability, occluded depth analysis, mCSM-binding affinity, and FoldX energy changes shortlisted only six mutations as being highly resistant. Finally, simulations of force field-based molecular dynamics (MD on wild type (WT) ERα) on six mERα variants (E380Q, S463P, Y537S, Y537C, Y537N, and D538G) were carried out to justify mechanism of the resistance. It was observed that these mutations increased the flexibility of the H12. A bonding analysis suggested that previously reported important residue His524 lost bonding upon mutation. Other parameters, such as PCA (principal component analysis), DCCM (dynamics cross-correlation), and FEL (free energy landscape), verified that the shortlisted mutations affect the H12 helix, which opens up the co-activator binding conformation. These results provide deep insight into the mechanism of relative resistance posed to fulvestrant due to mutations in breast cancer. This study will facilitate further understanding of the important aspects of designing specific and more effective drugs.