BJM School of Biosciences and Department of Biotechnology , Indian Institute of Technology Madras , Chennai 600036 , India.
J Phys Chem B. 2018 Apr 19;122(15):4239-4248. doi: 10.1021/acs.jpcb.7b12095. Epub 2018 Apr 6.
Cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesteryl esters (CEs) from antiatherogenic high-density lipoproteins to proatherogenic low-density lipoproteins. Inhibition of CETP is therefore being pursued as a potential strategy to reduce cardiovascular risk. The crystal structure of CETP has revealed the existence of two neutral CEs and two charged phospholipids (PLs) in its hydrophobic tunnel. This is in direct contrast to the other lipid-binding proteins that contain only two bound lipids. Moreover, previous animal studies on mice showed no detectable PL-transfer activity of CETP. Thus, the role of bound PLs in CETP is completely unknown. Here, we employ molecular dynamics simulations and free-energy calculations to unravel the primary effects of bound PLs on CETP structure and dynamics and attempt to correlate the observed changes to its function. Our results suggest that the structure of CETP is elastic and can attain different conformations depending on the state of bound PLs. In solution, these PLs maintain CETP in a bent-untwisted conformation that can uphold neutral lipids in its core tunnel. Results also suggest that although both PLs complement each other in their action, the C-terminal PL (C-PL) imparts greater influence on CETP by virtue of its tighter binding. Our finding fits very well with the recent inhibitor-bound CETP crystal structure, where the inhibitor displaced the N-terminal PL for binding to CETP's central domain without disrupting the binding of C-PL. We speculate that the observed increased flexibility of CETP in the absence of PLs could play a crucial role in its binding with lipoproteins and subsequent lipid-transfer activity.
胆固醇酯转移蛋白（CETP）促进胆固醇酯（CEs）从抗动脉粥样硬化的高密度脂蛋白向致动脉粥样硬化的低密度脂蛋白转移。因此，抑制 CETP 被认为是降低心血管风险的一种潜在策略。CETP 的晶体结构揭示了其疏水隧道中存在两种中性 CE 和两种带电荷的磷脂（PL）。这与其他仅包含两种结合脂质的脂质结合蛋白形成鲜明对比。此外，先前在小鼠上进行的动物研究表明 CETP 没有可检测到的 PL 转移活性。因此，结合 PL 在 CETP 中的作用完全未知。在这里，我们采用分子动力学模拟和自由能计算来揭示结合 PL 对 CETP 结构和动力学的主要影响，并尝试将观察到的变化与其功能相关联。我们的结果表明，CETP 的结构具有弹性，可以根据结合 PL 的状态达到不同的构象。在溶液中，这些 PL 使 CETP 保持弯曲未扭曲的构象，从而可以在其核心隧道中维持中性脂质。结果还表明，尽管两种 PL 在作用上相互补充，但 C 末端 PL（C-PL）通过其更紧密的结合对 CETP 产生更大的影响。我们的发现与最近的抑制剂结合 CETP 晶体结构非常吻合，其中抑制剂取代 N 末端 PL 与 CETP 的中心结构域结合，而不会破坏 C-PL 的结合。我们推测，在没有 PL 的情况下观察到的 CETP 增加的灵活性可能在其与脂蛋白的结合及其随后的脂质转移活性中发挥关键作用。
