Kazmirski S L, Daggett V
Department of Medicinal Chemistry, University of Washington, Seattle, WA, 98195-7610, USA.
J Mol Biol. 1998 Dec 4;284(3):793-806. doi: 10.1006/jmbi.1998.2192.
Molecular dynamics simulations of protein denaturation can complement and extend experimental studies of protein folding by providing atomic-level structural information about conformational transitions and any conformational states along the unfolding pathway. Previous unfolding simulations of hen egg-white lysozyme have resulted in intermediate structures with an unfolded alpha-domain and a structured beta-domain, which is inconsistent with experiment. In contrast, the beta-domain unfolded first in the two simulations presented here leaving a structured alpha-domain. Following this, intermediate states were identified that differ with respect to the packing of the helices and the elements of non-native structure adopted. The non-native structure is critical for explaining many of the experimental observations. Overall, the pooled ensemble of these intermediates is in agreement with the experimental data for the major kinetic intermediate, suggesting that the kinetic intermediate may be made up of distinct, but rapidly interconverting, partially folded conformations distinguished primarily by differences in helix packing.
蛋白质变性的分子动力学模拟可以通过提供有关构象转变以及沿解折叠途径的任何构象状态的原子级结构信息，来补充和扩展蛋白质折叠的实验研究。先前对鸡蛋清溶菌酶的解折叠模拟产生了具有未折叠α结构域和结构化β结构域的中间结构，这与实验结果不一致。相比之下，在此呈现的两个模拟中β结构域首先解折叠，留下一个结构化的α结构域。在此之后，识别出了中间状态，这些中间状态在螺旋堆积和所采用的非天然结构元件方面有所不同。非天然结构对于解释许多实验观察结果至关重要。总体而言，这些中间体的汇总集合与主要动力学中间体的实验数据一致，这表明动力学中间体可能由主要因螺旋堆积差异而区分的不同但快速相互转化的部分折叠构象组成。
