Insight into the molecular mechanism about lowered dihydrofolate binding affinity to dihydrofolate reductase-like 1 (DHFRL1)
Insight into the molecular mechanism about lowered dihydrofolate binding affinity to dihydrofolate reductase-like 1 (DHFRL1)
复制标题
深入了解二氢叶酸与二氢叶酸还原酶样 1 (DHFRL1) 结合亲和力降低的分子机制
DOI：
10.1007/s00894-013-2018-2
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发表时间：
2013-12-01
影响因子：
2.2
通讯作者：
Ji, Mingjuan
中科院分区：
文献类型：
--
作者：
Gao, Jian;Cui, Wei;Ji, Mingjuan
人二氢叶酸还原酶样 1 (DHFRL1) 已被确定为第二种人二氢叶酸还原酶 (DHFR)。尽管DHFRL1与人类DHFR具有较高的序列同源性，但二氢叶酸（DHF）与DHFRL1的结合亲和力较低，相应的分子机制仍不清楚。为了解决这个问题，我们通过分子动力学模拟研究了 DHF 与 DHFRL1 和 DHFR 的结合。此外，为了研究DHFR/DHFRL1的第24个残基在DHF结合中所起的作用，还研究了R24W DHFRL1突变体。范德华相互作用对于总 DHF 结合能更为重要，而人类 DHFR 和 DHFRL1 的 DHF 结合能之间的差异可归因于静电相互作用和极性去溶剂化自由能。更具体地说，DHF对DHFRL1的亲和力较低可主要归因于受Arg24的影响，DHFRL1的残基Arg32和Gln35与DHF的净静电相互作用减少。 DHFRL1中的Arg24侧链可以深入延伸到DHF和NADPH的结合位点，并通过空间效应干扰DHF结合，这在人类DHFR和R24W DHFRL1突变体中很少发生。此外，本工作还研究了 DHFRL1 中环 I 的构象。有趣的是，环构象类似于大肠杆菌DHFR的正常闭合状态，而不是人类DHFR的闭合状态。我们希望这项工作有助于了解 DHFRL1 的一般特征。
Human dihydrofolate reductase-like 1 (DHFRL1) has been identified as a second human dihydrofolate reductase (DHFR) enzyme. Although DHFRL1 have high sequence homology with human DHFR, dihydrofolate (DHF) exhibits a lowered binding affinity to DHFRL1 and the corresponding molecular mechanism is still unknown. To address this question, we studied the binding of DHF to DHFRL1 and DHFR by using molecular dynamics simulation. Moreover, to investigate the role the 24th residue of DHFR/DHFRL1 plays in DHF binding, R24W DHFRL1 mutant was also studied. The van der Waals interaction are more crucial for the total DHF binding energies, while the difference between the DHF binding energies of human DHFR and DHFRL1 can be attributed to the electrostatic interaction and the polar desolvation free energy. More specifically, lower DHF affinity to DHFRL1 can be mainly attributed to the reduction of net electrostatic interactions of residues Arg32 and Gln35 of DHFRL1 with DHF as being affected by Arg24. The side chain of Arg24 in DHFRL1 can extend deeply into the binding sites of DHF and NADPH, and disturb the DHF binding by steric effect, which rarely happens in human DHFR and R24W DHFRL1 mutant. Additionally, the conformation of loop I in DHFRL1 was also studied in this work. Interestingly, the loop conformation resemble to normal closed state ofEscherichia coliDHFR other than the closed state of human DHFR. We hope this work will be useful to understand the general characteristics of DHFRL1.