CETP输运胆固醇酯机理的分子动力学研究

Cholesteryl ester transfer protein (CETP) is the target protein for drug design to provent cardiovascular and cerebrovascular atherosclerotic disease that is ranked as number one human killer. The mechanism of cholesteryl esters (CE) transfer is a major and urgent scientific issues on human health. We will investigate the physical mechanism of CETP-mediated　cholesteryl esters (CE) transfer by means of molecule dynamics in this project. The optimal path of CE transfer in CETP will be recognized and characterized in the research. The depth and position of potential wells, and the height and position of potential barrier of CE transfer path will be determined quantitatively. The crucial amino acid sites to affect the CE transfer will be located. Through analyzing the global and local variations of CETP structure, the physical cause of CE transfer will be investigated. Having studied the latent intermediate states and their stability, we will further research how to change the CETP activity of CE transfer by adjusting the states. The way to hinder the CE transfer and reduce the activity of CETP will be discussed. By examinating the dynamics property of CE transfer, the physical cause of CE transfer will be investigated under physiological condition to reveal the mechanism of CE transfer mediated by CETP and the fashion of modulating the CETP activity. The studies in the project are scientifically significant on discovering the principle of CE transfer and developing drugs for anti-cardiovascular and cerebrovascular atherosclerotic disease.

胆固醇酯转移蛋白CETP是人类"头号杀手"心脑血管动脉粥样硬化疾病药物设计中的靶蛋白，其脂转运机理是一个关乎人类健康并亟待解决的重大问题。本项目拟采用分子动力学模拟方法，研究CETP传输胆固醇酯的物理机理。识别并表征CETP输运胆固醇酯的最优化路径，确定输运路径中势阱的位置与深度以及势垒的位置与高度，定位影响胆固醇酯传输的关键氨基酸位点。分析胆固醇酯传输过程中CETP整体和局部结构变化规律，探讨影响其传输的物理因素。分析胆固醇酯传输中潜在的中间态及其稳定性，研究如何通过调节中间态改变CETP的脂传输活性。探讨利用小分子阻止胆固醇酯传输，降低CETP活性的手段。研究胆固醇酯分子在CETP内传输的动力学特性，确认其在生理条件下穿越传输通道的物理原因，探讨CETP介导胆固醇酯转运的机理及调控CETP脂转运活性的方法。本项目研究对揭示脂转移物理规律、研发高效抗动脉粥样硬化药物都具有重要的科学意义。

胆固醇酯转运蛋白CETP的功能是调控生命体中的脂代谢，从高密度脂蛋白中的胆固醇酯转运到低密度或极低密度脂蛋白，并进行甘油三酯的逆向转运，为倍受瞩目的心脑血管动脉粥样硬化疾病预防与治疗的药物设计靶蛋白，其脂转运机理是一个关乎人类健康并亟待解决的重大问题。. 本项目研究了CETP传输胆固醇酯的分子物理机理，运用分子动力学模拟方法，分析了CETP介导胆固醇酯分子的输运过程，探讨CETP的胆固醇酯分子传输机制。确认CETP现有的抑制剂作用位点和潜在的新型抑制剂作用位点，并筛选新型抑制剂。. 该项目建立了无突变原生的CETP全原子三维结构模型，并建立了糖基化原生的CETP全原子三维结构模型。确定了CETP中部疏水腔和各疏水小腔从N端到C端联成一个通道，胆固醇酯分子能够的在其中传输，传输的优化路径位于该通道的中线。计算出了传输路径的胆固醇酯运动分子势能曲线，发现了传输路径中的势垒和势阱，势垒分别由氨基酸I15、L23与V198，I205、L206、M433与F263和F265形成，势阱分别由氨基酸R158h和F115与F167，F301与M412形成。正在临床试验的抑制剂torcetrapib、anacetrapib、evacetrapib，能使CETP内形成数条氢键，例如：Thr138 – Asn192，Arg37 – Glu186等，抑制胆固醇酯传输。提出了CETP的N端和C端开口为抑制剂药物设计的新型靶点，并计算模拟筛选出若干小分子抑制剂。. 该项目研究揭示了胆固醇酯分子转移机理，为开发CETP抑制药物奠定坚实的理论基础。不但对发展生物物理理论具有重要的学术意义，而且对开发CETP抑制药物具有指导意义。