title: Nucleotide-dependent conformational states of actin.
abstract: The influence of the state of the bound nucleotide (ATP, ADP-Pi, or ADP) on the conformational free-energy landscape of actin is investigated. Nucleotide-dependent folding of the DNase-I binding (DB) loop in monomeric actin and the actin trimer is carried out using all-atom molecular dynamics (MD) calculations accelerated with a multiscale implementation of the metadynamics algorithm. Additionally, an investigation of the opening and closing of the actin nucleotide binding cleft is performed. Nucleotide-dependent free-energy profiles for all of these conformational changes are calculated within the framework of metadynamics. We find that in ADP-bound monomer, the folded and unfolded states of the DB loop have similar relative free-energy. This result helps explain the experimental difficulty in obtaining an ordered crystal structure for this region of monomeric actin. However, we find that in the ADP-bound actin trimer, the folded DB loop is stable and in a free-energy minimum. It is also demonstrated that the nucleotide binding cleft favors a closed conformation for the bound nucleotide in the ATP and ADP-Pi states, whereas the ADP state favors an open confirmation, both in the monomer and trimer. These results suggest a mechanism of allosteric interactions between the nucleotide binding cleft and the DB loop. This behavior is confirmed by an additional simulation that shows the folding free-energy as a function of the nucleotide cleft width, which demonstrates that the barrier for folding changes significantly depending on the value of the cleft width.
authors.affiliation: Center for Biophysical Modeling and Simulation and Department of Chemistry, University of Utah, Salt Lake City, UT 84112-0850, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Pfaendtner
authors.forename: Davide
authors.initials: D
authors.lastname: Branduardi
authors.forename: Michele
authors.initials: M
authors.lastname: Parrinello
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Pollard
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Voth
mesh_terms: D000199:Actins / Q000737:chemistry*; D000244:Adenosine Diphosphate / Q000737:chemistry* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D003850:Deoxyribonuclease I / Q000378:metabolism; D006868:Hydrolysis; D011487:Protein Conformation; D017510:Protein Folding
chemical_list: D000199:Actins; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D003850:Deoxyribonuclease I