γ-Secretase is an intramembrane aspartyl-protease catalyzing the final step in the regulated intramembrane proteolysis of a large number of single-span type-1 transmembrane proteins. The most extensively studied substrates are the amyloid-β precursor protein (APP) and the NOTCH receptors. An important technique for the characterization of interactions and conformational changes enabling γ-secretase to perform hydrolysis within the confines of the membrane are molecular dynamics simulations on different time and length scales. Here, we review structural and dynamical features of γ−secretase and its substrates including flexibility descriptions from simulations and experiments. We address (1) conformational sampling of apo-enzyme and unbound substrates (exemplified for APP, NOTCH1 and the apparent non-substrate integrin β1), (2) substrate recruitment pathways, (3) conformational changes associated with the formation of the recognition complex, (4) cleavage-site unfolding upon interaction with the enzyme’s active site, (5) substrate processing after endoproteolysis, and (6) inhibition and modulation of γ-secretase. We conclude with still open questions and suggest further investigations in order to advance our understanding on how γ-secretase selects and processes substrates. This knowledge will improve the ability to better target substrates selectively for therapeutic applications.

γ-分泌酶是一种膜内天冬氨酰蛋白酶，可催化多种单跨1型跨膜蛋白的膜内蛋白水解的调控。研究最广泛的底物是β-淀粉样前体蛋白（APP）和NOTCH受体。表征相互作用和构象变化并使γ-分泌酶能够在膜范围内进行水解的一项重要技术是在不同时间和长度范围内进行分子动力学模拟。在这里，我们回顾了γ-分泌酶及其底物的结构和动力学特征，包括来自模拟和实验的灵活性描述。我们研究（1）脱辅酶和未结合底物的构象采样（示例为APP，NOTCH1和表观的非底物整合素β1），（2）底物募集途径，（3）与识别复合物形成相关的构象变化，（4）与酶的活性位点相互作用时切割位点展开，（5）内蛋白水解后的底物加工，以及（6）抑制和调节γ-分泌酶。我们以悬而未决的问题作结，并建议进一步研究，以增进我们对γ-分泌酶如何选择和处理底物的了解。这些知识将提高针对治疗应用选择性更好地靶向底物的能力。我们以尚待解决的问题作结，并建议进一步研究，以增进我们对γ-分泌酶如何选择和处理底物的了解。该知识将提高针对治疗应用选择性更好地靶向底物的能力。我们以悬而未决的问题作结，并建议进一步研究，以增进我们对γ-分泌酶如何选择和处理底物的了解。这些知识将提高针对治疗应用选择性更好地靶向底物的能力。