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首页> 外文期刊>The journal of physical chemistry, A. Molecules, spectroscopy, kinetics, environment, & general theory >An Enhanced Molecular Dynamics Study of HPPK—ATP Conformation Space Exploration and ATP Binding to HPPK
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An Enhanced Molecular Dynamics Study of HPPK—ATP Conformation Space Exploration and ATP Binding to HPPK

机译：HPPK-ATP构象空间探索和ATP与HPPK结合的增强的分子动力学研究

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摘要

HPPK (6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase) catalyzes the transfer of pyrophosphate from ATP to HP (6-hydroxymethyl-7,8-dihydropterin). This first reaction in the folate biosynthetic pathway is an important target for potential antimicrobial agents. In this work, the mechanism by which HPPK traps and binds ATP is studied by molecular dynamics (MD)-based methods. Based on the ternary crystal structure of HPPK with an ATP mimic and HP, a complex of ATPMg_2 and HPPK is simulated and found to undergo small conformational changes with conventional MD, as does also conventional MD when started from the apo crystal structure. The introduction of restraints in the MD that serve to move HPPK—ATP from its ternary complex (closed) to apo-like (open) forms shows that throughout the restraint path ATP remains bound to HPPK. That ATP remains bound suggests that there is an ensemble of conformations with ATP bound to HPPK that span the apo to more ligand-bound-like conformations, consistent with the pre-existing equilibrium hypothesis of ligand binding, whereby a ligand can select from and bind to a broad range of protein conformations. In the apo-like conformations, ATPMg_2 remains bound to HPPK through a number of mainly salt-bridge-like interactions between several negatively charged residues and the two magnesium cations. The introduction of a reweight method that enhances the sampling of MD by targeting explicit terms in the force field helps define the interactions that bind ATP to HPPK. Using the reweight method, conformational and center of mass motions of ATP, driven by the breaking and making of hydrogen bonds and salt bridges, are identified that lead to ATP separating from HPPK. An elastic normal mode (ENM) approach to opening the ternary complex and closing the apo crystal structures was carried out. The ENM analysis of the apo structure analysis shows one mode that does have a closing motion of HPPK loops, but the direction does not correlate strongly with the loop motions that are required for forming the ternary complex.
机译：HPPK（6-羟甲基-7,8-二氢蝶呤酶）催化焦磷酸从ATP转移到HP（6-羟甲基-7,8-二氢蝶呤）。叶酸生物合成途径中的第一个反应是潜在抗菌剂的重要目标。在这项工作中，通过基于分子动力学（MD）的方法研究了HPPK捕获和结合ATP的机制。基于具有ATP模拟物和HP的HPPK的三元晶体结构，模拟了ATPMg_2和HPPK的复合物，发现常规MD的构象变化很小，从脱辅基晶体结构开始的常规MD也是如此。在MD中引入限制剂后，可将HPPK-ATP从其三元复合物（封闭）转变为载脂蛋白（开放）形式，这表明在整个抑制路径中，ATP仍与HPPK结合。 ATP保持结合状态表明与HPPK结合的ATP具有一系列构象，这些构象跨越载脂蛋白至更多的配体结合样构象，这与先前存在的配体结合平衡假设相符，从而使配体可以选择并结合广泛的蛋白质构象。在载脂蛋白样构象中，ATPMg_2仍通过几个带负电荷的残基与两个镁阳离子之间的许多盐桥样相互作用与HPPK结合。通过以力场中的显式术语为目标的重加权方法的引入，可以增强MD的采样，有助于定义将ATP与HPPK结合的相互作用。使用重重法，确定了由氢键和盐桥的断裂和产生所驱动的ATP的构象和质心运动，从而导致ATP与HPPK分离。进行了弹性常模（ENM）方法以打开三元复合物并关闭脱辅基晶体结构。载脂蛋白结构分析的ENM分析显示，一种模式确实具有HPPK环的闭合运动，但方向与形成三元复合物所需的环运动没有很强的相关性。

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