Molecular Dynamics of the Long Neurotoxin LSIII

• Published in: Biochemistry (Easton) Vol. 42; no. 49; pp. 14443 - 14451
• Main Authors: Connolly, Peter J, Stern, Alan S, Turner, Christopher J, Hoch, Jeffrey C
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 16-12-2003
• Subjects: Computer Simulation; Elapid Venoms - chemistry; Elapid Venoms - metabolism; Models, Molecular; Neurotoxins - chemistry; Neurotoxins - metabolism; Nuclear Magnetic Resonance, Biomolecular; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Receptors, Cholinergic - chemistry; Reptilian Proteins; Structural Homology, Protein; Thermodynamics
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi034687m

Long neurotoxins bind tightly and specifically to the nicotinic acetylcholine receptor (AChR) in postsynaptic membranes and are useful for exploring the biology of synapses. In crystallographic studies of long neurotoxins the principal binding loop appears disordered, but the NMR solution structure of the long neurotoxin LSIII revealed significant local order, even though the loop is disordered with respect to the globular core. A possible mechanism for conferring global disorder while preserving local order is rigid-body motion of the loop about a hinge region. Here we report investigations of LSIII dynamics based on 13Cα magnetic relaxation rates and molecular dynamics simulation. The relaxation rates and MD simulation both confirm the hypothesis of rigid-body motion of the loop and place bounds on the extent and time scale of the motion. The bending motion of the loop is slow compared to the rapid fluctuations of individual dihedral angles, reflecting the collective nature and largely entropic free energy profile for hinge bending. The dynamics of the central binding loop in LSIII illustrates two distinct mechanisms by which molecular dynamics directly impacts biological activity. The relative rigidity of key residues involved in recognition at the tip of the central binding loop lowers the otherwise substantial entropic cost of binding. Large excursions of the loop hinge angle may endow the protein with structural plasticity, allowing it to adapt to conformational changes induced in the receptor.