Protein complex formation by acetylcholinesterase and the neurotoxin fasciculin-2 appears to involve an induced-fit mechanism

Abstract

Specific, rapid association of protein complexes is essential for all forms of cellular existence. The initial association of two molecules in diffusion-controlled reactions is often influenced by the electrostatic potential. Yet, the detailed binding mechanisms of proteins highly depend on the particular system. A complete protein complex formation pathway has been delineated by using structural information sampled over the course of the transformation reaction. The pathway begins at an encounter complex that is formed by one of the apo forms of neurotoxin fasciculin-2 (FAS2) and its high-affinity binding protein, acetylcholinesterase (AChE), followed by rapid conformational rearrangements into an intermediate complex that subsequently converts to the final complex as observed in crystal structures. Formation of the intermediate complex has also been independently captured in a separate 20-ns molecular dynamics simulation of the encounter complex. Conformational transitions between the apo and liganded states of FAS2 in the presence and absence of AChE are described in terms of their relative free energy profiles that link these two states. The transitions of FAS2 after binding to AChE are significantly faster than in the absence of AChE; the energy barrier between the two conformational states is reduced by half. Conformational rearrangements of FAS2 to the final liganded form not only bring the FAS2͞AChE complex to lower energy states, but by controlling transient motions that lead to opening or closing one of the alternative passages to the active site of the enzyme also maximize the ligand's inhibition of the enzyme.conformational transitions ͉ protein-protein binding

Dissection of the high rate constant for the binding of a ribotoxin to the ribosome

“…This suggestion is supported by molecular dynamics simulations of the SRL RNA, which show that the tetraloop has only limited flexibility on a 25-ns time scale (24). The apparent ''induced fit'' implicated here is reminiscent of the observations of a recent molecular dynamics study (25), in which binding to a protein partner was found to speed up the conformational transitions of another protein significantly.…”

Conformer Selection and Induced Fit in Flexible Backbone Protein–Protein Docking Using Computational and NMR Ensembles

“…4a). Computer simulations have provided evidence for both conformational gating 44 and an IF mechanism 45 of binding to AChe. The ensemble representing the unbound state of FAS2 that was generated from the unbound crystal structure contained conformational variability in all three loops, but most noticeably in loop II (Fig.…”

Replica exchange simulations of transient encounter complexes in protein–protein association

“…Deviations may in part be caused by approximations in our procedure (in particular, not including the Mn 2ϩ labels in the simulations). In addition, the underlying coarsegrained energy function ignores atomic detail (13,28), and the resulting small k B T-scale errors can significantly affect the relative populations.…”

“…protein binding ͉ transient nonspecific encounter complexes ͉ paramagnetic relaxation enhancement ͉ bacterial phosphotransferase system E xperimental and theoretical studies have provided evidence that transient nonspecific encounter complexes play an important role in protein binding and function (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). The formation of weakly bound nonspecific complexes, often dominated by long-range electrostatic interactions, enhances the on-rate of binding by increasing the interaction cross-section and reducing the conformational space to be searched on the path to the specific complex.…”