C99, a naturally occurring peptide, is a precursor of the amyloid β-peptide (Aβ) and plays an important role in the so-called amyloidogenic pathway of degradation of amyloid precursor protein. While the effect of C99’s dimerization is not clearly determined, it has been hypothesized that the dimerization protects C99 from being cleaved further. Cholesterol (CHOL) is known to interact with C99 and its presence in high concentrations has been linked to an increase in the production of Aβ; however, to what extent this is correlated, and how, has not yet been determined. In this study, we systematically examine the effect of increasing cholesterol concentration on the homodimerization propensity of C99, combining unbiased atomistic molecular dynamics simulations with biased simulations using a coarse grained resolution. Through the use of umbrella sampling, we show how the presence of high levels of CHOL destabilizes the interaction between two C99 monomers. The interaction pattern between the two C99s has shifted several residues, from the N-terminal end of the transmembrane region toward the corresponding C-terminal in the presence of CHOL. The umbrella sampling shows that the presence of high levels of CHOL led to a decrease of the disassociation energy by approximately 3 kJ/mol. In conclusion, this suggests that increasing CHOL destabilizes the interaction between the two C99 monomers, which may possibly cause an increase in the production of Aβ₄₂.

中文翻译：

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胆固醇对C99二聚化的影响——分子建模视角

C99 是一种天然存在的肽，是淀粉样蛋白β肽 (A β )的前体，在淀粉样蛋白前体蛋白降解的所谓淀粉样生成途径中起重要作用。虽然 C99 的二聚化的影响没有明确确定，但已经假设二聚化保护 C99 不被进一步切割。已知胆固醇 (CHOL) 与 C99 相互作用，其高浓度存在与 A β产量增加有关; 然而，这在多大程度上相关，以及如何相关，尚未确定。在这项研究中，我们系统地检查了胆固醇浓度增加对 C99 同二聚化倾向的影响，将无偏原子分子动力学模拟与使用粗粒度分辨率的有偏模拟相结合。通过使用伞状采样，我们展示了高水平 CHOL 的存在如何破坏两个 C99 单体之间的相互作用。在 CHOL 存在的情况下，两个 C99 之间的相互作用模式已将几个残基从跨膜区的 N 端移向相应的 C 端。伞形采样显示高水平 CHOL 的存在导致解离能降低约 3 kJ/mol。综上所述，β ₄₂。