Computational analysis of the binding affinities of the natural-product cyclopentapeptides argifin and argadin to chitinase B from Serratia marcescens
Computational analysis of the binding affinities of the natural-product cyclopentapeptides argifin and argadin to chitinase B from Serratia marcescens
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DOI：
10.1016/j.bmc.2008.02.017
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发表时间：
2008-04-01
影响因子：
3.5
通讯作者：
Hirono, Shuichi
中科院分区：
文献类型：
--
作者：
Gouda, Hiroaki;Yanai, Yuichi;Hirono, Shuichi
采用分子动力学(MD)模拟和分子力学泊松-玻尔兹曼表面积(MM-PBSA)方法研究了天然产物环五肽几丁质酶抑制剂精氨酸和精氨酸与粘质沙雷氏菌几丁质酶B(CHIB)的相互作用。Argadin对Chib的抑制常数为20 nM，比Argifin高3个数量级(K-I=33,000 nM)。MM-PBSA自由能分析得到精氨酸和精氨酸络合物的绝对结合自由能分别为-6.98和-11.16千卡/摩尔。这些估计值与由实验KI值(精氨酸和精氨酸络合物的KI分别为-6.36和-10.92千卡/摩尔)得到的自由能符合得很好。能量分析表明，范德华能和非极性溶剂化能驱动精氨酸和精氨酸的结合。我们发现，精氨酸与精氨酸的结合能比精氨酸高出约12kcal/mol，这是造成精氨酸与精氨酸结合自由能差异的主要原因。特别是，Chib的W220和W403被发现有助于更有利的van der Waals与Aradin的相互作用。我们还设计了具有更好结合亲和力的精氨酸衍生物，其中精氨酸的组成氨基酸残基被突变为具有较大侧链的氨基酸残基。用D-色氨酸取代精氨酸的D-丙氨酸的衍生物似乎具有与精氨酸相同的结合亲和力。(C)2008爱思唯尔有限公司。保留所有权利。
Molecular dynamics (MD) simulations and the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method were applied to study the interaction of the natural-product cyclopentapeptide chitinase inhibitors argifin and argadin with chitinase B (ChiB) from Serratia marcescens. Argadin inhibited ChiB with an inhibition constant (Ki) value of 20 nM, which was three orders of magnitude greater than that of argifin (K-i = 33,000 nM). The MM-PBSA free-energy analysis provided absolute binding free energies of -6.98 and -11.16 kcal/mol for the argifin and argadin complexes, respectively. These estimates were in good agreement with the free energies derived from the experimental Ki values (-6.36 and -10.92 kcal/mol for the argifin and argadin complexes, respectively). The energetic analysis revealed that the van der Waals and nonpolar solvation energies drove the binding of both argifin and argadin. We found that the binding of argadin gained similar to 12 kcal/mol more van der Waals energy than that of argifin, which was mainly responsible for the difference in binding free energy between argifin and argadin. In particular, W220 and W403 of ChiB were found to contribute to the more favorable van der Waals interaction with argadin. We also designed argifin derivatives with better binding affinity, in which a constituent amino-acid residue of argifin was mutated to one with a bulky side chain. The derivative in which D-Ala of argifin was replaced with D-Trp appeared to possess a binding affinity that was equally potent to that of argadin. (C) 2008 Elsevier Ltd. All rights reserved.