Inward opening (IO) to outward opening (OO) 'catalytic transition' and OO to IO 'relaxation' of P-glycoprotein: to investigate the role of helices in efflux through targeted molecular dynamics simulation.

In silico pharmacology Pub Date : 2025-07-16 eCollection Date: 2025-01-01 DOI:10.1007/s40203-025-00389-3
Pranabesh Mandal, Priyanka Rani, Durg Vijay Singh
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Abstract

P-glycoprotein (P-gp) is a membrane protein that effluxes xenobiotics across cell membranes via ATP hydrolysis. It is overexpressed mainly in cancer cells and is responsible for multidrug resistance by effluxing chemotherapeutic molecules. To unearth the coordinated mechanism and function of different domains i.e., nucleotide binding domain (NBD), transmembrane domain (TMD) and transmembrane helices (TMHs) in catalysis, human P-gp was modelled in Inward Opening (IO) and Outward Opening (OO) states and further subjected to targeted molecular dynamics (tMD) simulations. Structural transition frames between IO ⇌ OO were obtained from the clustering of tMD simulation trajectories. Protein model quality scores (ProSA Z-scores) were evaluated for conformational states. The results showed that the IO → OO transition is an energetically uphill process requiring a major structural transition involving 131 distinct conformational states, coupled with ATP hydrolysis. In contrast, the OO → IO relaxation, crucial for resetting the transporter, does not follow the same transition pathway and is an energetically downhill process involving only 90 states, indicating a faster and distinct mechanism. The helix pairs 1&7 and 6&12 are observed to be relatively static, forming the core of the TMD, while pairs 3&9 and 4&10 are moderately dynamic, and pairs 5&11 and 2&8 are highly dynamic, located more peripherally. The static and dynamic nature and position of these helix pairs justify their respective roles in substrate binding and efflux, and these findings may provide insight into the design and development of next-generation P-gp inhibitors.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00389-3.

向内开口(IO)到向外开口(OO)p -糖蛋白的“催化转变”和从OO到IO的“松弛”:通过靶向分子动力学模拟研究螺旋在外排中的作用。
p -糖蛋白(P-gp)是一种膜蛋白,通过ATP水解将异种生物排出细胞膜。它主要在癌细胞中过度表达,并通过外排化疗分子导致多药耐药。为了揭示核苷酸结合结构域(NBD)、跨膜结构域(TMD)和跨膜螺旋结构域(TMHs)在催化过程中的协调机制和功能,我们以内向开放(IO)和外向开放(OO)状态为模型,对人P-gp进行了靶向分子动力学(TMD)模拟。通过对tMD模拟轨迹的聚类,得到了IO和OO之间的结构过渡框架。蛋白质模型质量评分(ProSA z -score)评估构象状态。结果表明,从IO到OO的转变是一个能量上坡的过程,需要131种不同构象状态的主要结构转变,并伴有ATP水解。相比之下,对于转运体重置至关重要的OO→IO弛豫并不遵循相同的转变途径,而是一个能量下降的过程,只涉及90个状态,表明一个更快和独特的机制。观察到螺旋对1&7和6&12相对静止,形成TMD的核心,而对3&9和4&10是中等动态的,对5&11和2&8是高度动态的,位于更外围。这些螺旋对的静态和动态性质和位置证明了它们各自在底物结合和外排中的作用,这些发现可能为下一代P-gp抑制剂的设计和开发提供见解。补充信息:在线版本包含补充资料,提供地址为10.1007/s40203-025-00389-3。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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