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化学进展 2021, Vol. 33 Issue (10): 1797-1811 DOI: 10.7536/PC200912 前一篇   后一篇

• 综述 •

抗冻蛋白抗冻机制的分子模拟研究

张维佳1, 邵学广1,2,*(), 蔡文生1,*()   

  1. 1 南开大学化学学院分析科学研究中心 天津市生物传感与分子识别重点实验室 天津 300071
    2 南开大学药物化学生物学国家重点实验室 天津 300071
  • 收稿日期:2020-09-04 修回日期:2020-10-27 出版日期:2021-10-20 发布日期:2021-07-29
  • 通讯作者: 邵学广, 蔡文生
  • 基金资助:
    国家自然科学基金项目(21773125); 国家自然科学基金项目(21775076); 国家自然科学基金项目(22073050); 中央高校基本科研基金项目(63201043)
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Molecular Simulation of the Antifreeze Mechanism of Antifreeze Proteins

Weijia Zhang1, Xueguang Shao1,2(), Wensheng Cai1()   

  1. 1 Research Center for Analytical Sciences, College of Chemistry, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Nankai University,Tianjin 300071, China
    2 State Key Laboratory of Medicinal Chemical Biology, Nankai University,Tianjin 300071, China
  • Received:2020-09-04 Revised:2020-10-27 Online:2021-10-20 Published:2021-07-29
  • Contact: Xueguang Shao, Wensheng Cai
  • Supported by:
    National Natural Science Foundation of China(21773125); National Natural Science Foundation of China(21775076); National Natural Science Foundation of China(22073050); Fundamental Research Funds for the Central Universities, Nankai University(63201043)

抗冻蛋白能使生物体在寒冷环境下生存,具有极大的潜在应用价值。近年来,人们对抗冻蛋白开展了广泛的研究,但其抗冻机理还未明确。本文阐述了抗冻蛋白的功能特性和结构特征,并从结构的角度对其抗冻机制方面的分子模拟研究成果进行了综述。另一方面,对目前已知晶体结构的29个野生型抗冻蛋白的结构特性进行了分析,发现在整个抗冻蛋白表面和在冰结合位点处都存在亲水残基与水形成氢键和疏水残基与类冰结构特异性结合的特点。然后,探讨了抗冻蛋白的二级结构、冰结合位点残基的疏水性与抗冻活性之间的关系。最后,从结构的角度讨论了抗冻蛋白的机制和影响抗冻活性的因素并简要总结了仿生抗冻材料设计和应用的研究进展。

关键词： 抗冻蛋白, 仿生抗冻材料, 热滞活性, 吸附-抑制机制, ACW机制, 分子动力学模拟

Antifreeze proteins enable organisms to survive in subzero environments. Owing to this unique property, antifreeze proteins have great potential application in a variety of fields. Antifreeze proteins have been extensively studied, but the antifreeze mechanism is still fragmentary, due to the limitation of experimental means. Molecular dynamics, as a method to simulate the interaction between molecules at the atomic level, has been widely used in the study of the mechanism of antifreeze proteins in recent years. In this paper, the functional and structural characteristics of antifreeze proteins, and the research progress of antifreeze mechanisms are described and reviewed from the perspective of structure. Furthermore, the structural characteristics of 29 wild-type antifreeze proteins with known crystal structure, and the hydrophobicity of the residues distributed on the protein surface and at the ice-binding site are analyzed. Both the affinity of the interaction between hydrophilic residues and water and the specificity of the interaction between hydrophobic residues and ice-like water are found either on the surface or at the ice-binding site of antifreeze proteins. The relationship between the secondary structure, the hydrophobicity of the residues at ice-binding site and the antifreeze activity is discussed. Finally, the mechanisms of antifreeze proteins and the factors affecting the antifreeze activity are discussed from the perspective of structure, and the progress in the design and application of bioinspired antifreeze materials with low toxicity and cost is briefly summarized.

Contents

1 Introduction

2 Functional characteristics of antifreeze proteins

3 Structure and mechanisms of antifreeze proteins

3.1 Fish AFPs

3.2 Insect AFPs

3.3 Plant AFPs

3.4 Microorganism AFPs

3.5 Similarities and differences of antifreeze mechanisms of different antifreeze proteins

3.6 Structural factors affecting antifreeze activity

4 Bioinspired antifreeze materials

5 Conclusion and outlook

Key words: antifreeze proteins, bioinspired antifreeze materials, thermal hysteresis activity, adsorption-inhibition mechanism, ACW mechanism, molecular dynamics simulations
()
图1 冰晶示意图。(a) 冰晶的不同晶面示意图,绿色区域表示基面,蓝色区域表示主棱面,紫色区域表示锥面。(b) 冰晶在a轴方向的生长受到抑制时,形成双棱锥形状。(c) 冰晶在a轴和c轴方向的生长均受到抑制时,形成六棱盘形状
Fig. 1 Schematic representation of ice crystal.(a) Different ice planes of ice crystal, the green area represents the basal plane, the blue area represents the primary prism plane and the purple area represents the pyramidal plane.(b) Ice crystal forms a hexagonal bipyramid shape, when the growth of it in the a-axis direction is inhibited.(c) Ice crystal forms a hexagonal plate shape, when the growth of it in both a-axis and c-axis directions is inhibited
图2 抗冻蛋白其他特性示意图。(a) 微生物分泌的AFPs为其创造了一个液态栖息地;(b) MpAFP将细菌粘附在冰面上
Fig. 2 Schematic representation of functional characteristics.(a) Microorganisms secreted AFPs to maintain a local liquid environment;(b) MpAFP serves to adhere bacteria to ice surfaces
图3 吸附-抑制机制示意图。绿色半球体代表抗冻蛋白,青色柱体代表冰晶,自由的水分子没有显示
Fig. 3 Schematic representation of adsorption-inhibition mechanism, the green hemispheres represent antifreeze proteins, the cyan pillars represent ice crystals. Free water molecules are not shown
图4 抗冻机理示意图。(a) 氢键假说;(b) 疏水作用;(c) ACW机制。冰结合位点以苏氨酸为例,绿色半球体代表抗冻蛋白,青色柱体代表冰晶,蓝色小球代表锚定结合水,黑色虚线代表氢键,自由的水分子没有显示
Fig. 4 Schematic representation of antifreeze mechanism.(a) hydrogen bonding hypothesis,(b) hydrophobic effect,(c) ACW mechanism. An example of ice binding site is threonine, the green hemispheres represent antifreeze proteins, the cyan pillars represent ice crystals, the blue spheres represent anchored clathrate water, the black dotted lines represent hydrogen bonds. Free water molecules are not shown
图5 局部融化机制示意图。绿色半球体代表抗冻蛋白,青色柱体代表冰晶,深蓝色区域代表过冷水,自由的水分子没有显示
Fig. 5 Schematic representation of “local melting” mechanism, the green hemispheres represent antifreeze proteins, the cyan pillars represent ice crystals, the deep blue area represents supercooled water. Free water molecules are not shown
图6 AFPⅠ (PDB ID: 1WFA)和泛素(PDB ID: 1UBQ)的结构特性对比图
Fig. 6 Comparison of surface structural characteristics of AFPⅠ(PDB ID: 1WFA) and ubiquitin(PDB ID: 1UBQ)
图7 (a) Ca2+-非依赖型BrAFP (PDB ID: 2ZIB)和(b) Ca2+-依赖型抗冻蛋白hAFP (PDB ID: 2PY2)的假定冰结合平面对比图,绿色的小球代表Ca2+,黄色虚线区域代表Ca2+结合环
Fig. 7 Comparison of putative IBSs of(a) Ca2+-independent BrAFP(PDB ID: 2ZIB) and(b) Ca2+-dependent hAFP(PDB ID: 2PY2), the green sphere represents Ca2+ and the yellow dotted line area represents Ca2+-binding loop
图8 3种AFPⅡ的结构特性对比图
Fig. 8 Surface structural characteristics of three AFPⅡ
图9 8种AFPⅢ的结构特性
Fig. 9 Surface structural characteristics of eight AFPⅢ
图10 2种TxT基序的昆虫抗冻蛋白(PDB ID: 1L0S,1EZG)冰结合序列示意图
Fig. 10 Ice-binding sites of two insect AFPs with TxT motifs(PDB ID: 1L0S,1EZG)
表1 抗冻蛋白的结构特征、性质和机理总结
Table 1 Summary of structural characteristics, properties and mechanisms of antifreeze proteinsa
Origin and type Structural characteristics PDB ID R1
(%)b		 R2
(%)C		 R3
(%)d		 R4 (%)e Antifreeze Mechnism ref.
Fish AFPⅠ α-helix, 65% alanine 1WFA 68 33 14 0 a hydration mediated AFP
adsorption mechanism/“local
melting” mechanism		 33, 79
AFPⅡ Globular, 2α-helix+2 β-sheet 2ZIB 52 12 24 38 ACW mechanism 84, 88
2PY2 35 41 28 24
6JK4 32 0 26 50
AFPⅢ Globular, no dominant nonpolar
amino acids		 1MSI 31 56 19 0 a hydration mediated AFP
adsorption mechanism		 67, 92, 93, 95
1OPS 32 50 14 0
1UCS 38 56 19 0
1GZI 39 56 19 0
3QF6 27 56 19 0
1HG7 38 56 16 0
4UR4 37 56 15 0
1AME 36 56 16 0
AFPⅣ 4 antiparallel helical bundles, Glu-rich The Adsorption-Inhibition
Hypothesis		 98
AFGP (Ala-Thr-Ala)n with a
disaccharide moiety(Galβ1-
3GalNAcα1-) attached to each Thr residue		 The Adsorption-Inhibition
Hypothesis/Perturbation of Long-
Range Water Dynamics		 17, 29, 31, 34, 35
Insect Polyproline type II 3BOI 34 47 18 7 “local melting” mechanism 104
2PNE 38 47 21 7
β-solenoid, seven coils of
TCTxSxxCxxAx repeats		 1EZG 16 44 14 0 ACW mechanism 28, 76
β-solenoid, flat β-sheet of
Thr-x-Thr motifs		 1EWW 19 27 19 0 16, 69
1L0S 21 20 19 0
1M8N 24 33 16 0

Flat β-solenoid		 4DT5 13 29 20 4
β-solenoid, Thr-rich, Cys- rich 1L1I 15 44 15 0
Plant
Micro-organism		 Bacteria β-solenoid 3ULT 15 50 14 0 ACW mechanism 50
β-solenoid 3P4G 20 5 29 18 ACW mechanism 32
β-solenoid with a triangular cross-section alongside an α-helix 3WP9 21 32 25 10 ACW mechanism 15, 118, 119
4NU2 28 38 16 5
6EIO 32 20 8 10
Fungus β-solenoid with a triangular cross-section alongside an α-helix 3UYU 24 41 22 13 ACW mechanism 14, 51, 120, 121
5B5H 24 48 6 8
6A8K 24 50 10 5
3VN3 25 35 13 12
Ubiquitin Globular 1UBQ 16 41 Non-antifreeze protein(as a reference)
图11 植物抗冻蛋白(PDB ID: 3ULT)冰结合序列示意图。正面为“a”面,背面为“b”面
Fig. 11 Ice-binding site of plant AFP(PDB ID: 3ULT). The front is “a” side, and the back is “b” side
图12 仿生抗冻材料。(a) 不同形状的抗冻金胶体[135]。(b)氧化准碳氮化物量子点OQCNs[136]。(c) 昆虫TmAFP(上)和合成染料自组装形成的超分子冰生长抑制剂(下)的侧面(左)和正面(右)对比示意图[11],红色小球代表羟基,蓝色小球代表氮原子,灰色部分代表碳骨架。(d)基于自组装肽的超分子冰生长抑制剂示意图[137]
Fig. 12 Bioinspired antifreeze materials.(a) different shapes of antifreeze gold colloids[135]. Copyright(2019) American Chemical Society.(b) oxidized quasi-carbon nitride quantum dots OQCNs[136]. Copyright John Wiley & Sons.(c) side and front views of TmAFP, an AFP from insects, and a supramolecular ice growth inhibitor[11], the blue spheres represent the amine groups, the gray part represents the carbon skeleton and the red spheres represent the hydroxyl groups. Copyright 2016, American Chemical Society.(d) schematic of the supramolecular ice growth inhibitors based on self-assembling peptides[137]. Copyright 2019, American Chemical Society
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