Unbinding of Retinoic Acid from the Retinoic Acid Receptor by Random Expulsion Molecular Dynamics

Carlsson, Peter; Burendahl, Sofia; Nilsson, Lennart

doi:10.1529/biophysj.106.082917

Cited by 67 publications

(81 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The most likely egress pathway and the exit mechanisms can be suggested by statistical analysis of the simulation trajectories. RAMD has been applied to study a variety of ligand release events including substrate and product release from cytochrome P450 enzymes (Luedemann et al, 2000;Schleinkofer et al, 2005;Wade et al, 2004;Winn et al, 2002), unbinding of retinoic acid from the retinoic acid receptor (Carlsson et al, 2006), retinal release from rhodopsin (Wang et al, 2007), ligand unbinding from the vitamin D receptor (Perakyla 2009), and product release from haloalkane dehalogenases Pavlova et al, 2009).…”

Section: Ramd Simulationsmentioning

confidence: 99%

Retinal release from opsin in molecular dynamics simulations

Wang

Duan

2010

J of Molecular Recognition

View full text Add to dashboard Cite

The crystal structures of opsin in the ligand-free and the G-protein-interacting states showed two inter-helical openings between transmembrane (TM) helices TM1 and TM7 and between TM5 and TM6 near the extracellular side that were thought to serve as the retinal uptake and release gates. However, it is unclear which opening is for 11-cis-retinal uptake or all-trans-retinal release although speculations have been proposed based on the structural features of opsin and retinal. In this work, we simulated the exit process of all-trans-retinal from the ligand-free opsin structure by the classical molecular dynamics (MD) and random acceleration molecular dynamics (RAMD). In the 64 ns classical MD simulation, retinal remained in the receptor but moved significantly toward the TM5-TM6 opening and almost inserted into the opening after 50 ns. Complete exit was observed in 114 out of 160 RAMD trajectories with the TM5-TM6 opening being the predominant egress gate while egress from the TM1-TM7 opening was observed in only a few trajectories when relatively large acceleration was applied and large structural alteration of the protein resulted. These results suggest that photolyzed all-trans-retinal is likely released through the TM5-TM6 opening. Based on the unidirectional mechanism of retinal exchange suggested by experiment, we speculate that the TM1-TM7 opening serves as the 11-cis-retinal uptake gate. The spatial occupancy maps of retinal computed from the 160 RAMD trajectories further indicated that retinal experienced significant interactions with the receptor during the exit process. The implications of these findings for disease mechanisms of rhodopsin mutants are discussed.

show abstract

Section: Ramd Simulationsmentioning

confidence: 99%

Retinal release from opsin in molecular dynamics simulations

Wang

Duan

2010

J of Molecular Recognition

View full text Add to dashboard Cite

show abstract

“…As new structural models of NR LBDs become available, answers to these questions are being unveiled with experimental and theoretical methods. [18][19][20][21][22][23][24][25][26] The description of the denaturation mechanisms of any protein is very challenging. Detection of molecular mechanisms and intermediate states is not always accessible experimentally.…”

Section: Introductionmentioning

confidence: 99%

On the Denaturation Mechanisms of the Ligand Binding Domain of Thyroid Hormone Receptors

et al. 2009

View full text Add to dashboard Cite

The ligand binding domain (LBD) of nuclear hormone receptors adopts a very compact, mostly R-helical structure that binds specific ligands with very high affinity. We use circular dichroism spectroscopy and high-temperature molecular dynamics simulations to investigate unfolding of the LBDs of thyroid hormone receptors (TRs). A molecular description of the denaturation mechanisms is obtained by molecular dynamics simulations of the TRR and TR LBDs in the absence and in the presence of the natural ligand Triac. The simulations show that the thermal unfolding of the LBD starts with the loss of native contacts and secondary structure elements, while the structure remains essentially compact, resembling a molten globule state. This differs from most protein denaturation simulations reported to date and suggests that the folding mechanism may start with the hydrophobic collapse of the TR LBDs. Our results reveal that the stabilities of the LBDs of the TRR and TR subtypes are affected to different degrees by the binding of the isoform selective ligand Triac and that ligand binding confers protection against thermal denaturation and unfolding in a subtype specific manner. Our simulations indicate two mechanisms by which the ligand stabilizes the LBD: (1) by enhancing the interactions between H8 and H11, and the interaction of the region between H1 and the Ω-loop with the core of the LBD, and (2) by shielding the hydrophobic H6 from hydration.

show abstract

“…Increasing the temperature of the system [9] [18] may have as a consequence overestimation of the entropic part of the free energy by facilitating transitions that might not be observed at lower temperatures. Applying a randomly oriented force is limited to qualitative treatments, such as in investigating ligand egress from, and access to, cytochrome P450cam [19 -21], retinoic acid receptor [22], Gprotein-coupled receptor rhodopsin [23], hexameric insulin [15], b2-adrenergic receptor [24], liver fatty acid binding protein [25], vitamin D receptor [26], haloalkane dehalogenases [27] [28], and voltage-gated Kv1.5 potassium channel [29]. However, although qualitative in character, RAMD simulations profit from choosing the direction of the external force direction randomly.…”

mentioning

confidence: 99%

On the Egress of Carbon Monoxide from Myoglobin

Pietra

2011

Chemistry & Biodiversity

View full text Add to dashboard Cite

The pathways of escape of carbon monoxide (CO) from sperm whale myoglobin were investigated by means of a biased form of all-atoms molecular dynamics (RAMD), whereby a weak, randomly oriented force is applied to the center of mass of CO. The force only persists if the direction taken by CO continues for a given period of time, otherwise a new direction is randomly chosen. A statistically significant number of RAMD runs gave distinct responses according to the level of approximations used for the model. Thus, with rigid bonds to all H-atoms, several portals for CO egress toward the solvent, besides the main H64 gate, were identified, like in recently published unbiased massive MD, six orders of magnitude acceleration of CO escape in RAMD notwithstanding. In contrast, by removing the approximation of rigid bonds in the model, only one of these extra portals was identified, besides the H64 portal. Sticking to this all-free-bonds model, Perutzs early suggestion that the H64 imidazole must rotate out toward the solvent in order that CO can cross the H64 gate was directly implemented. RAMD Simulations with this model led to CO egress from the H64 gate only, reconciling theory with experiments.

show abstract

Unbinding of Retinoic Acid from the Retinoic Acid Receptor by Random Expulsion Molecular Dynamics

Cited by 67 publications

References 36 publications

Retinal release from opsin in molecular dynamics simulations

Retinal release from opsin in molecular dynamics simulations

On the Denaturation Mechanisms of the Ligand Binding Domain of Thyroid Hormone Receptors

On the Egress of Carbon Monoxide from Myoglobin

Contact Info

Product

Resources

About