Pathway for large-scale conformational change in annexin V.
Crystallographic studies have shown that the binding of calcium to domain III of annexin V is accompanied by a large conformational change involving surface exposure of Trp187. Here we examine this conformational transition using computer simulation. It is found that the burial of Trp187 is accompanied by a large increase in conformational strain, compensated by improved protein-protein interaction energies. A low energy pathway for the conformational change is determined using the conjugate peak refinement method [Fischer, S., and Karplus, M. (1992) Chem. Phys. Lett. 194, 252-261] with solvent effects taken into account using nonuniform charge scaling. The pathway obtained is complex, involving >300 dihedral angle transitions and the complete unwinding of one helix. Acidic residues play a key role in the conformational pathway, via a succession of direct hydrogen bonds with the indole ring of Trp187. This finding is discussed in the light of experimentally determined pH, calcium ion and mutational effects on the conformational transition.
Sopkova-De Oliveira Santos
J
J
Section de Biophysique des Protéines et des Membranes, Département de Biologie Cellulaire et Moléculaire, CEA-Saclay, 91191 Gif-sur-Yvette Cedex, France.
Fischer
S
S
Guilbert
C
C
Lewit-Bentley
A
A
Smith
J C
JC
D017304:Annexin A5 / Q000737:chemistry*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D014364:Tryptophan / Q000737:chemistry
D017304:Annexin A5; D014364:Tryptophan