title: Exploring Binding Mechanisms in Nuclear Hormone Receptors by Monte Carlo and X-ray-derived Motions.
abstract: In this study, we performed an extensive exploration of the ligand entry mechanism for members of the steroid nuclear hormone receptor family (androgen receptor, estrogen receptor α, glucocorticoid receptor, mineralocorticoid receptor, and progesterone receptor) and their endogenous ligands. The exploration revealed a shared entry path through the helix 3, 7, and 11 regions. Examination of the x-ray structures of the receptor-ligand complexes further showed two distinct folds of the helix 6-7 region, classified as "open" and "closed", which could potentially affect ligand binding. To improve sampling of the helix 6-7 loop, we incorporated motion modes based on principal component analysis of existing crystal structures of the receptors and applied them to the protein-ligand sampling. A detailed comparison with the anisotropic network model (an elastic network model) highlights the importance of flexibility in the entrance region. While the binding (interaction) energy of individual simulations can be used to score different ligands, extensive sampling further allows us to predict absolute binding free energies and analyze reaction kinetics using Markov state models and Perron-cluster cluster analysis, respectively. The predicted relative binding free energies for three ligands binding to the progesterone receptor are in very good agreement with experimental results and the Perron-cluster cluster analysis highlighted the importance of a peripheral binding site. Our analysis revealed that the flexibility of the helix 3, 7, and 11 regions represents the most important factor for ligand binding. Furthermore, the hydrophobicity of the ligand influences the transition between the peripheral and the active binding site.
authors.affiliation: Cardiovascular & Metabolic Disease (CVMD), AstraZeneca, Mölndal, Sweden. Electronic address: christoph.grebner@astrazeneca.com.
authors.forename: Christoph
authors.initials: C
authors.lastname: Grebner
authors.affiliation: Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lecina
authors.affiliation: Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Barcelona, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Gil
authors.affiliation: Cardiovascular & Metabolic Disease (CVMD), AstraZeneca, Mölndal, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Ulander
authors.affiliation: Discovery Sciences, AstraZeneca, Mölndal, Sweden.
authors.forename: Pia
authors.initials: P
authors.lastname: Hansson
authors.affiliation: Discovery Sciences, AstraZeneca, Mölndal, Sweden.
authors.forename: Anita
authors.initials: A
authors.lastname: Dellsen
authors.affiliation: Respiratory, Inflammation, and Autoimmunity (RIA), AstraZeneca, Mölndal, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Tyrchan
authors.affiliation: Discovery Sciences, AstraZeneca, Mölndal, Sweden. Electronic address: karl.edman@astrazeneca.com.
authors.forename: Karl
authors.initials: K
authors.lastname: Edman
authors.affiliation: Cardiovascular & Metabolic Disease (CVMD), AstraZeneca, Mölndal, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Hogner
authors.affiliation: Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. Electronic address: victor.guallar@bsc.es.
authors.forename: Victor
authors.initials: V
authors.lastname: Guallar
mesh_terms: D007700:Kinetics; D008024:Ligands; D008390:Markov Chains; D008958:Models, Molecular; D009010:Monte Carlo Method; D009068:Movement; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics; D014965:X-Rays
chemical_list: D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear