Connecting protein conformational dynamics with catalytic function as illustrated in dihydrofolate reductase.
Connecting protein conformational dynamics with catalytic function as illustrated in dihydrofolate reductase.
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DOI：
10.1021/bi301559q
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发表时间：
2013-03-26
期刊：
影响因子：
2.9
通讯作者：
Gao J
中科院分区：
文献类型：
--
作者：
Fan Y;Cembran A;Ma S;Gao J
QM/MM联合分子动力学模拟表明，由于M42W/G121V双突变，二氢叶酸还原酶(DHFR)的M20环构象动力学在氢化物转移的过渡态受到严重限制。因此，与野生型DHFR相比，双突变酶具有更低的激活熵，即更高的熵势垒，并改变了动力学同位素效应的温度依赖性。有趣的是，在野生型dhfr和双突变体中，平均供体-受体距离在Michaelis复合态(约3.5？)和过渡态(2.7？)下基本相同。结果发现，在M42W/G121V双突变体中，在闭合构象中形成了一个额外的氢键来稳定M20环。计算结果反映了一个类似的目标，旨在精确地敲除不同双突变体N23PP/S148A中M20环的动态灵活性。
Combined QM/MM molecular dynamics simulations reveal that the M20 loop conformational dynamics of dihydrofolate reductase (DHFR) is severely restricted at the transition state of the hydride transfer as a result of the M42W/G121V double mutation. Consequently, the double mutant enzyme has a reduced entropy of activation, i.e., increased entropic barrier, and altered temperature dependence of kinetic isotope effects in comparison with wild-type DHFR. Interestingly, both in the wild-type DHFR and the double mutant, the average donor-acceptor distances are essentially the same in the Michaelis complex state (about 3.5 Å) and the transition state (2.7 Å). It was found that an additional hydrogen bond is formed to stabilize the M20 loop in the closed conformation in the M42W/G121V double mutant. The computational results reflect a similar aim designed to knock out precisely the dynamic flexibility of the M20 loop in a different double mutant, N23PP/S148A.
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DOI：
10.1016/j.str.2009.06.008
发表时间：
2009-08-12
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
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通讯作者：
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DOI：
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发表时间：
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期刊：
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