Neural disorders research experiments

Dynamic and Kinetic Elements of µ-Opioid Receptor Functional Selectivity.

WU tags:

Description

[Experiment image]

While the therapeutic effect of opioids analgesics is mainly attributed to µ-opioid receptor (MOR) activation leading to G protein signaling, their side effects have mostly been linked to β-arrestin signaling. To shed light on the dynamic and kinetic elements underlying MOR functional selectivity, we carried out close to half millisecond high-throughput molecular dynamics simulations of MOR bound to a classical opioid drug (morphine) or a potent G protein-biased agonist (TRV-130). Statistical analyses of Markov state models built using this large simulation dataset combined with information theory enabled, for the first time: a) Identification of four distinct metastable regions along the activation pathway, b) Kinetic evidence of a different dynamic behavior of the receptor bound to a classical or G protein-biased opioid agonist, c) Identification of kinetically distinct conformational states to be used for the rational design of functionally selective ligands that may eventually be developed into improved drugs; d) Characterization of multiple activation/deactivation pathways of MOR, and e) Suggestion from calculated transition timescales that MOR conformational changes are not the rate-limiting step in receptor activation.

Publications

  • Kapoor A, Martinez-Rosell G, Provasi D, de Fabritiis G, Filizola M, Dynamic and Kinetic Elements of µ-Opioid Receptor Functional Selectivity. Scientific reports 2017. doi:10.1038/s41598-017-11483-8

BadgeRankNameCredit
wat1 Syracuse University849,294,000.00
wat2 RaymondFO*551,227,600.00
wat3 Retvari Zoltan474,189,150.00
wat4 Rion Family362,332,900.00
wat5 jjch347,974,625.00
wat6 Gunde296,886,825.00
wat7 Stoneageman293,348,100.00
wat8 AND280,535,475.00
wat9 Beyond241,162,075.00
wat10 Grzegorz Roman Granowski200,853,150.00
Number of contributors: 1656

Multibody cofactor and substrate molecular recognition in the myo-inositol monophosphatase enzyme.

WU tags:

Description

[Experiment image]

Molecular recognition is rarely a two-body protein-ligand problem, as it often involves the dynamic interplay of multiple molecules that together control the binding process. Myo-inositol monophosphatase (IMPase), a drug target for bipolar disorder, depends on 3 Mg(2+) ions as cofactor for its catalytic activity. Although the crystallographic pose of the pre-catalytic complex is well characterized, the binding process by which substrate, cofactor and protein cooperate is essentially unknown. Here, we have characterized cofactor and substrate cooperative binding by means of large-scale molecular dynamics. Our study showed the first and second Mg(2+) ions identify the binding pocket with fast kinetics whereas the third ion presents a much higher energy barrier. Substrate binding can occur in cooperation with cofactor, or alone to a binary or ternary cofactor-IMPase complex, although the last scenario occurs several orders of magnitude faster. Our atomic description of the three-body mechanism offers a particularly challenging example of pathway reconstruction, and may prove particularly useful in realistic contexts where water, ions, cofactors or other entities cooperate and modulate the binding process.

Publications

  • Ferruz N, Tresadern G, Pineda-Lucena A, De Fabritiis G, Multibody cofactor and substrate molecular recognition in the myo-inositol monophosphatase enzyme. Scientific reports 2016. doi:10.1038/srep30275

BadgeRankNameCredit
wat1 RaymondFO*422,144,250.00
wat2 Retvari Zoltan341,321,000.00
wat3 Stoneageman292,333,450.00
wat4 HA-SOFT, s.r.o.262,358,500.00
wat5 Herb253,839,450.00
wat6 Rick A. Sponholz252,672,250.00
wat7 Roald230,229,750.00
wat8 Beyond207,112,500.00
wat9 Orange_1050199,475,250.00
wat10 BruceR188,746,000.00
Number of contributors: 4128

Uncovering the role of membrane lipids in modulating enzyme activity

WU tags: FAAH

Description

Lipids and the membranes they form are one of the basic functional units of all life, from bacteria up to humans. They have historically received less reseach attention than other biomolecules because they were seen primarily as scaffolding on which proteins, DNA, and RNA could function and segragate. Lately, however, it is becoming clear that lipids and their composition in membranes play key functional roles, facilitating or attenuating various processes like signaling and protein activity. In a recent work published in Biochemical Journal, we provide a mechanistic explanation of how membrane lipids modify the activity of the enzyme Fatty Acid Amide Hydrolase (FAAH) by facilitating binding. Additionally, we show the unbiased binding of the lipid andandamide to the enzyme. On the right you can see a video showing the binding process. This enzyme plays an essential role in terminating signaling in the endocannabinoid system, and is important for a wide spectrum of biological function, including memory, immune response, hunger and pain.

This research was conducted in collaboration with Dr. Enrico Dainese from the University of Teramo, Italy.

Publications

  • E. Dainese, G. De Fabritiis, A. Sabatucci, S. Oddi, C. Angelucci, C. Di Pancrazio, T. Giorgino, N. Stanley, B. Cravatt, and M. Maccarrone, Membrane lipids are key-modulators of the endocannabinoid-hydrolase FAAH, Biochem J. 2014 Feb 1;457(3):463-72. PDF can be found here

BadgeRankNameCredit
wat1 Stoneageman156,749,803.00
wat2 Retvari Zoltan105,138,548.00
wat3 Venec84,456,492.00
wat4 HA-SOFT, s.r.o.84,299,745.00
wat5 comfortw59,820,396.00
wat6 Helmholdt49,291,642.00
wat7 alephnull46,986,897.00
wat8 Herb36,786,111.00
wat9 CTAPbIi35,661,739.00
wat10 Ketzer734,941,558.00
Number of contributors: 3864

Molecular simulations of the D2 Dopamine receptor under physiological ionic strength conditions

WU tags: JAN

Description

Sodium ions have been shown to play an important role in the binding of antipsychotic drugs to the D2 Dopamine receptor. Understanding the sodium-induced mechanism is of great interest for future drug design in the treatment of schizophrenia.
By means of molecular dynamics we simulate the mobility of sodium ions and its effect on the dynamic properties of the D2 receptor under physiological ionic strength conditions.
GPUGRID technology allows us to handle an all-atom system in which D2 receptor is embedded in a membrane bilayer with a total of 61,000 atoms and accelerates the computational performance up to microseconds.

Research conducted in collaboration with Dr. Jana Selent from Universitat Pompeu Fabra.

Publications

  • J. Selent, F. Sanz, M. Pastor and G. De Fabritiis, Induced Effects of Sodium Ions on Dopaminergic G-Protein Coupled Receptors, PLOS Computational Biology, 6, e1000884 (2010)

BadgeRankNameCredit
wat1 Stoneageman2,943,112.00
wat2 dak16402,617,782.00
wat3 JasonDrson2,084,773.00
wat4 Eliezer2,052,745.00
wat5 xdrv2,024,943.00
wat6 Paul D. Buck1,825,838.00
wat7 JackOfAll1,638,314.00
wat8 UL11,627,753.00
wat9 INFRNL1,578,370.00
wat10 dataman1,355,684.00
Number of contributors: 3118