Bui Jennifer M, Radic Zoran, Taylor Palmer, McCammon J Andrew
Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, California 92093-0365, USA.
Biophys J. 2006 May 1;90(9):3280-7. doi: 10.1529/biophysj.105.075564. Epub 2006 Feb 10.
The neurotoxin fasciculin-2 (FAS2) is a picomolar inhibitor of synaptic acetylcholinesterase (AChE). The dynamics of binding between FAS2 and AChE is influenced by conformational fluctuations both before and after protein encounter. Submicrosecond molecular dynamics trajectories of apo forms of fasciculin, corresponding to different conformational substates, are reported here with reference to the conformational changes of loop I of this three-fingered toxin. This highly flexible loop exhibits an ensemble of conformations within each substate corresponding to its functions. The high energy barrier found between the two major substates leads to transitions that are slow on the timescale of the diffusional encounter of noninteracting FAS2 and AChE. The more stable of the two apo substates may not be the one observed in the complex with AChE. It seems likely that the more stable apo form binds rapidly to AChE and conformational readjustments then occur in the resulting encounter complex.
神经毒素束丝菌素-2（FAS2）是突触乙酰胆碱酯酶（AChE）的皮摩尔级抑制剂。FAS2与AChE之间的结合动力学受蛋白质相遇前后构象波动的影响。本文报道了对应于不同构象亚态的束丝菌素脱辅基形式的亚微秒分子动力学轨迹，并参考了这种三指毒素环I的构象变化。这个高度灵活的环在每个亚态内呈现出与其功能相对应的一系列构象。在两个主要亚态之间发现的高能垒导致在非相互作用的FAS2和AChE扩散相遇的时间尺度上的缓慢转变。两种脱辅基亚态中较稳定的一种可能不是在与AChE形成的复合物中观察到的那种。似乎更稳定的脱辅基形式会迅速与AChE结合，然后在形成的相遇复合物中发生构象重新调整。
