Joshi Harshad V, Jedrzejas Mark J, de Groot Bert L
Computational Biomolecular Dynamics Group, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany.
Proteins. 2009 Jul;76(1):30-46. doi: 10.1002/prot.22316.
Hyaluronan lyase (Hyal) is a surface enzyme occurring in many bacterial organisms including members of Streptococcus species. Streptococcal Hyal primarily degrades hyaluronan-substrate (HA) of the extracellular matrix. This degradation appears to facilitate the spread of this bacterium throughout host tissues. Unlike purely endolytic degradation of its other substrates, unsulfated chondroitin or some chondroitin sulfates, the degradation of HA by Hyal proceeds by processive exolytic cleavage of one disaccharide at a time following an initial endolytic cut. Molecular dynamics (MD) studies of Hyal from Streptococcus pneumoniae are presented that address the enzyme's molecular mechanism of action and the role of domain motions for processive functionality. The analysis of extensive sub-microsecond MD simulations of this enzyme action on HA-substrates of different lengths and the connection between the domain dynamics of Hyal and the translocation of the HA-substrate reveals that opening/closing and twisting domain motions of the Hyal are intimately linked to processive HA degradation. Enforced simulations confirmed this finding as the domain motions in SpnHyal were found to be induced by enforced substrate translocation. These results establish the dynamic interplay between Hyal flexibility and substrate translocation and provide insight into the processive mechanism of Hyal.
透明质酸酶（Hyal）是一种存在于许多细菌中的表面酶，包括链球菌属的成员。链球菌Hyal主要降解细胞外基质中的透明质酸底物（HA）。这种降解似乎有助于这种细菌在宿主组织中扩散。与它对其他底物（未硫酸化的软骨素或一些硫酸软骨素）的纯粹内切降解不同，Hyal对HA的降解是在初始内切切割后，通过每次逐个切割一个二糖的连续外切过程进行的。本文展示了对肺炎链球菌Hyal的分子动力学（MD）研究，该研究探讨了该酶的分子作用机制以及结构域运动对连续功能的作用。对该酶作用于不同长度HA底物的大量亚微秒MD模拟分析，以及Hyal结构域动力学与HA底物转运之间的联系，揭示了Hyal的打开/关闭和扭曲结构域运动与连续HA降解密切相关。强制模拟证实了这一发现，因为发现肺炎链球菌Hyal中的结构域运动是由强制底物转运诱导的。这些结果确立了Hyal灵活性与底物转运之间的动态相互作用，并为Hyal的连续作用机制提供了深入了解。
