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Molecular dynamics simulations of an engineered T4 lysozyme exclude helix to sheet transition, and provide insights into long distance, intra-protein switchable motion.
Protein Science ( IF 8 ) Pub Date : 2019-11-08 , DOI: 10.1002/pro.3780
Laurence Biggers 1 , Hadeer Elhabashy 2 , Edward Ackad 3 , Mohammad S Yousef 4
Affiliation  

An engineered variant of T4 lysozyme serves as a model for studying induced remote conformational changes in a full protein context. The design involves a duplicated surface helix, flanked by two loops, that switches between two different conformations spanning about 20 Å. Molecular dynamics simulations of the engineered protein, up to 1 μs, rule out α-helix to β-sheet transitions within the duplicated helix as suggested by others. These simulations highlight how the use of different force fields can lead to radical differences in the structure of the protein. In addition, Markov state modeling and transition path theory were employed to map a 6.6 μs simulation for possible early intermediate states and to provide insights into the onset of the switching motion. The putative intermediates involve the folding of one helical turn in the C-terminal loop through energy driven, sequential rearrangement of nearby salt bridges around the key residue Arg63. These results provide a first step towards understanding the energetics and dynamics of a rather complicated intra-protein motion.

中文翻译:

工程T4溶菌酶的分子动力学模拟排除了螺旋向片层的过渡,并提供了远距离,蛋白内可切换运动的见解。

T4溶菌酶的工程变体用作研究全蛋白环境下诱导的远程构象变化的模型。该设计包括一个重复的表面螺旋,两侧是两个环,在两个大约20Å的不同构象之间切换。正如其他人所建议的那样,长达1μs的工程蛋白分子动力学模拟排除了重复螺旋内从α螺旋到β折叠的转变。这些模拟突出显示了如何使用不同的力场会导致蛋白质结构的根本差异。此外,采用马尔可夫状态建模和过渡路径理论为可能的早期中间状态映射了6.6 µs仿真,并提供了对切换运动开始的见解。推测的中间体包括通过能量驱动的,围绕关键残基Arg63的附近盐桥的顺序重排,使C末端回路中的一个螺旋圈折叠。这些结果为了解相当复杂的蛋白内运动的能量学和动力学提供了第一步。
更新日期:2020-01-13
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