Comparison of the dynamics for ground-state and transition-state structures in the active site of catechol O-methyltransferase
Comparison of the dynamics for ground-state and transition-state structures in the active site of catechol O-methyltransferase
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DOI：
10.1021/ja000265d
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发表时间：
2000-08-02
影响因子：
15
通讯作者：
Bruice, TC
中科院分区：
文献类型：
--
作者：
Lau, EY;Bruice, TC
采用三种1-ns分子动力学（MD）模拟方法研究了儿茶酚o -甲基转移酶在含有儿茶酚、儿茶酚酸和过渡态时的活性位点结构，发现含有儿茶酚酸和过渡态时酶活性位点的物理性质非常相似。儿茶酚酸盐和过渡态模拟计算的s -腺苷- l-蛋氨酸（AdoMet）甲基10埃内活性位点残基的均方根偏差和位置波动相似，这些残基的平均溶剂可达表面积几乎相同。在基态模拟中发现，AdoMet和酶之间的相互作用对于AdoMet进入接近攻击构象（NACs）至关重要，这与过渡态几何形状相似。Tyr68的CB影响AdoMet的甲基碳与儿茶酚酸离子氧之间的距离。Met40和Asp141的主酰胺羰基之间的相互作用控制了AdoMet相对于儿茶酚酸盐的角度定位，当相互作用消失时，AdoMet的硫碳和甲基碳与儿茶酚酸盐的离子氧形成的角度减小，不再符合NAC标准。将这3个MD模拟与本实验室之前的量子力学计算结果进行比较，表明该酶从e -s到e - ts的催化能力不是由于过渡态的稳定，而是由于儿茶酚o -甲基转移酶的活性位点将反应物排列成与过渡态非常相似的构象的能力。总的来说，在E.S到E.TS的过程中，人们也会考虑将儿茶酚酸和AdoMet溶解作为驱动力。
Three 1-ns molecular dynamics (MD) simulations have been used to study the active-site structure of catechol O-methyltransferase when containing catechol, catecholate, or the transition state, It was found that the physical properties of the enzyme active sites are very similar when containing either catecholate or the transition state. The calculated root-mean-squared deviation and positional fluctuations of the active-site residues within 10 Angstrom of the methyl group of S-adenosyl-L-methionine (AdoMet) for the catecholate and transition-state simulations are similar, and the average solvent accessible surface areas for these residues are almost identical. It was found in the ground-state simulation with catecholate that interactions between AdoMet and the enzyme are critical in positioning AdoMet into near attack conformers (NACs) which resemble the transition-state geometry. The CB of Tyr68 influences the distance between the methyl carbon of AdoMet and the ionized oxygen of catecholate. Interactions between the backbone amide carbonyls of Met40 and Asp141 control the angular positioning of the AdoMet relative to catecholate, When the interactions dissipated, the angle formed by the sulfur and methyl carbon of AdoMet and ionized oxygen of catecholate decreased and no longer fulfilled the NAC criteria. Comparisons of these 3 MD simulations in combination with results from previous quantum mechanical calculations from this lab suggest that the catalytic power of this enzyme in going from E.S to E.TS is not due to transition-state stabilization but from the ability of the active site of catechol O-methyltransferase to arrange the reactants into conformers that closely resemble the transition state. Overall, in E.S going to E.TS one would also consider as a driving force catecholate and AdoMet desolvation.