嗜热冷休克蛋白去折叠的全原子分析
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摘要
嗜热冷休克蛋白对于保证生物体功能的正常运作发挥着重要作用,其独特功能和β桶状结构使其非常适合作为研究蛋白质折叠的模型。采用分子动力学模拟的方法,对其在550 K高温下的去折叠行为进行了统计分析。结果表明:嗜热冷休克蛋白的去折叠过程存在多条路径,其去折叠行为主要归因于带电残基间所形成的离子对,离子对的分布决定了不同β股间的作用强弱,从而影响了其动力学行为。同时还发现疏水核心回旋半径的变化与周围水分子数量的变化相一致,说明水分子与去折叠行为之间的关系满足并发机制。
Thermophilic cold shock proteins play an important role in ensuring the normal functioning of organisms. Their unique functions and β-barrel structure make them very suitable for models in the process of studying protein folding. In this study,molecular dynamics simulation was used to analyze the unfolding behavior at 550 K. The results showed that there were multiple paths in the unfolding process of thermophilic cold shock proteins, of which the unfolding behavior was mainly attributed to the ion pairs formed between charged residues. The distribution of ion pairs determined the strength of the interaction among different β-strands, which affected the dynamic behavior of thermophilic cold shock proteins. We also found that the change of the radius of gyration of the hydrophobic core was consistent with the change of the number of water molecules around it, indicating that the relationship between water molecules and unfolding behavior satisfied the concurrency mechanism.
Thermophilic cold shock proteins play an important role in ensuring the normal functioning of organisms. Their unique functions and β-barrel structure make them very suitable for models in the process of studying protein folding. In this study,molecular dynamics simulation was used to analyze the unfolding behavior at 550 K. The results showed that there were multiple paths in the unfolding process of thermophilic cold shock proteins, of which the unfolding behavior was mainly attributed to the ion pairs formed between charged residues. The distribution of ion pairs determined the strength of the interaction among different β-strands, which affected the dynamic behavior of thermophilic cold shock proteins. We also found that the change of the radius of gyration of the hydrophobic core was consistent with the change of the number of water molecules around it, indicating that the relationship between water molecules and unfolding behavior satisfied the concurrency mechanism.
引文
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[2] GUO Q, MINTIER G, MA-EDMONDS M, et al.‘Cold shock’ increases the frequency of homology directed repair gene editing in induced pluripotent stem cells[J]. Scientific reports, 2018, 8(1):2080.
[3] YANG H J, SHI X, JU F, et al. Cold shock induced protein RBM3 but not mild hypothermia protects human SH-SY5Y neuroblastoma cells from MPP+-induced neurotoxicity[J]. Frontiers in neuroscience, 2018, 12:298.
[4] SU J G, HAN X M, ZHAO S X, et al. Impacts of the charged residues mutation S48E/N62H on the thermostability and unfolding behavior of cold shock protein:insights from molecular dynamics simulation with Gōmodel[J]. Journal of molecular modeling, 2016, 22(4):1-11.
[5] RENNELLA E, Sára T, JUEN M, et al. RNA binding and chaperone activity of the E. coli cold-shock protein CspA[J].Nucleic acids research, 2017, 45(7):4255-4268.
[6] LIU M, WEISS M A, ARUNAGIRI A, et al. Biosynthesis,structure, and folding of the insulin precursor protein[J].Diabetes, obesity and metabolism, 2018, 20(2):28-50.
[7] CHENG B, LI Y, MA L, et al. Interaction between amyloidogenic proteins and biomembranes in protein misfolding diseases:Mechanisms, contributors, and therapy[J].Biochimica et biophysica acta(BBA)-biomembranes,2018, 1860(9):1876-1888.
[8] SOTOMAYOR M, SCHULTEN K. Single-molecule experiments in vitro and in silico[J]. Science, 2007, 316(5828):1144-1148.
[9] MUELLLER U, PERL D, SCHMID F X, et al. Thermal stability and atomic-resolution crystal structure of the bacillus caldolyticus cold shock protein[J]. Journal of molecular biology, 2000, 297(4):975-988.
[10] HUMPHREY W, DALKE A, SCHULTEN K. VMD:visual molecular dynamics[J]. Journal of molecular graphics,1996, 14(1):33-38.
[11] PHILLIPS J C, BRAUN R, WANG W, et al. Scalable molecular dynamics with NAMD[J]. Journal of computational chemistry, 2005, 26(16):1781-1802.
[12] JORGENSEN W L, CHANDRASEKHAR J, MADURA J D, et al. Comparison of simple potential functions for simulating liquid water[J]. Journal of chemical physics,1983, 79(2):926-935.
[13] NERIA E, FISCHER S, KARPLUS M. Simulation of activation free energies in molecular systems[J]. The journal of chemical physics, 1996, 105(5):1902-1921.
[14] RYCKAERT J P, CICCOTTI G, BERENDSEN H J C.Numerical integration of the cartesian equations of motion of a system with constraints:molecular dynamics of nalkanes[J]. Journal of computational physics, 1977, 23(3):327-341.
[15] DARDEN T, YORK D, PEDERSEN L. Particle mesh ewald:an N·log(N)method for ewald sums in large systems[J]. The journal of chemical physics, 1998, 98(12):10089-10092.
[16] ESSMANN U, PERERA L, BERKOWITZ M L, et al. A smooth particle mesh ewald method[J]. Journal of chemical physics, 1995, 103(19):8577-8593.
[17] SAGUI C, DARDEN T A. Molecular dynamics simulations of biomolecules:long-range electrostatic effects[J]. Annual review of biophysics and biomolecular structure, 1999, 28(1):155-179.
[18] TOUKMAJI A, SAGUI C, BOARD J, et al. Efficient particle-mesh ewald based approach to fixed and induced dipolar interactions[J]. The journal of chemical physics,2000, 113(24):10913-10927.
[19] WEIKL T R, DILL K A. Folding rates and low-entropyloss routes of two-state proteins[J]. Journal of molecular biology, 2003, 329(3):585-598.
[20] ZHOU H X. How do biomolecular systems speed up and regulate rates[J]. Physical biology, 2005, 2(3):1-25.
[21] RHEE Y M, SORIN E J, JAYACHANDRAN G, et al.Simulations of the role of water in the protein-folding mechanism[J]. Proceedings of the national academy of sciences of the United States of America, 2004, 101(17):6456-6461.