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Biophys J, August 2002, p. 681-698, Vol. 83, No. 2

Protein Unfolding Transitions in an Intrinsically Unstable Annexin Domain: Molecular Dynamics Simulation and Comparison with Nuclear Magnetic Resonance Data

Tru Huynh,* Jeremy C. Smith,*dagger and Alain Sanson*

 *Commissariat à l'Energie Atomique-Saclay, Département de Biologie Joliot-Curie/Service de Biophysique des Fonctions Membranaires and Unité de Recherche Associée Centre National de la Recherche Scientifique 2096, 91191 Gif-sur-Yvette Cedex, France; and  dagger Lehrstuhl für Biocomputing, Interdiszplinäres Zentrum für Wissenschaftliches Rechnen, Universität Heidelberg, Im Neuenheimer Feld 368, 69120 Heidelberg, Germany

Unfolding transitions of an intrinsically unstable annexin domain and the unfolded state structure have been examined using multiple ~10-ns molecular dynamics simulations. Three main basins are observed in the configurational space: native-like state, compact partially unfolded or intermediate compact state, and the unfolded state. In the native-like state fluctuations are observed that are nonproductive for unfolding. During these fluctuations, after an initial loss of ~20% of the core residue native contacts, the core of the protein transiently completely refolds to the native state. The transition from the native-like basin to the partially unfolded compact state involves ~75% loss of native contacts but little change in the radius of gyration or core hydration properties. The intermediate state adopts for part of the time in one of the trajectories a novel highly compact salt-bridge stabilized structure that can be identified as a conformational trap. The intermediate-to-unfolded state transition is characterized by a large increase in the radius of gyration. After an initial relaxation the unfolded state recovers a native-like topology of the domain. The simulated unfolded state ensemble reproduces in detail experimental nuclear magnetic resonance data and leads to a convincing complete picture of the unfolded domain.

Biophys J, August 2002, p. 681-698, Vol. 83, No. 2
© 2002 by the Biophysical Society   0006-3495/02/08/681/18  $2.00




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Copyright © 2002 by the Biophysical Society.