Disordered Structural Ensembles of Vasopressin and Oxytocin and Their Mutants

Yedvabny, Eugene; Nerenberg, Paul S.; So, Clare; Head‐Gordon, Teresa

doi:10.1021/jp505902m

Cited by 34 publications

(55 citation statements)

References 54 publications

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“…Regarding protein disorder levels, these receptors follow a similar trend as observed for the ligand OXT and AVP nonapeptides, which have been described as intrinsically disordered (Yedvabny et al , 2015). The suggestion that the level of disorder is maintained throughout evolution to promote a wide range of interaction among proteins and other molecules has been subject of intense debate (Schlessinger et al.…”

Section: Discussionsupporting

confidence: 57%

Oxytocin and arginine vasopressin receptor evolution: implications for adaptive novelties in placental mammals

et al. 2016

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Oxytocin receptor (OXTR) and arginine vasopressin receptors (AVPR1a, AVPR1b, and AVPR2) are paralogous genes that emerged through duplication events; along the evolutionary timeline, owing to speciation, numerous orthologues emerged as well. In order to elucidate the evolutionary forces that shaped these four genes in placental mammals and to reveal specific aspects of their protein structures, 35 species were selected. Specifically, we investigated their molecular evolutionary history and intrinsic protein disorder content, and identified the presence of short linear interaction motifs. OXTR seems to be under evolutionary constraint in placental mammals, whereas AVPR1a, AVPR1b, and AVPR2 exhibit higher evolutionary rates, suggesting that they have been under relaxed or experienced positive selection. In addition, we describe here, for the first time, that the OXTR, AVPR1a, AVPR1b, and AVPR2 mammalian orthologues preserve their disorder content, while this condition varies among the paralogues. Finally, our results reveal the presence of short linear interaction motifs, indicating possible functional adaptations related to physiological and/or behavioral taxa-specific traits.

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Section: Discussionsupporting

confidence: 57%

Oxytocin and arginine vasopressin receptor evolution: implications for adaptive novelties in placental mammals

et al. 2016

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“…The TIP4P-Ew water model reproduces a number of experimental measurements for disordered cyclic peptides, vasopressin and oxytocin (43), and amyloid-β proteins (38,44). The new TIP4P-D model has increased water dispersion interactions and better approximates global conformational properties of intrinsically disordered proteins (IDPs) (36,45) and FG repeats in particular (35), enabling more accurate simulation of protein dynamics.…”

Section: Resultsmentioning

confidence: 97%

Slide-and-exchange mechanism for rapid and selective transport through the nuclear pore complex

Raveh

Karp

Sparks

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

131

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Nucleocytoplasmic transport is mediated by the interaction of transport factors (TFs) with disordered phenylalanine-glycine (FG) repeats that fill the central channel of the nuclear pore complex (NPC). However, the mechanism by which TFs rapidly diffuse through multiple FG repeats without compromising NPC selectivity is not yet fully understood. In this study, we build on our recent NMR investigations showing that FG repeats are highly dynamic, flexible, and rapidly exchanging among TF interaction sites. We use unbiased long timescale all-atom simulations on the Anton supercomputer, combined with extensive enhanced sampling simulations and NMR experiments, to characterize the thermodynamic and kinetic properties of FG repeats and their interaction with a model transport factor. Both the simulations and experimental data indicate that FG repeats are highly dynamic random coils, lack intrachain interactions, and exhibit significant entropically driven resistance to spatial confinement. We show that the FG motifs reversibly slide in and out of multiple TF interaction sites, transitioning rapidly between a strongly interacting state and a weakly interacting state, rather than undergoing a much slower transition between strongly interacting and completely noninteracting (unbound) states. In the weakly interacting state, FG motifs can be more easily displaced by other competing FG motifs, providing a simple mechanism for rapid exchange of TF/FG motif contacts during transport. This slide-and-exchange mechanism highlights the direct role of the disorder within FG repeats in nucleocytoplasmic transport, and resolves the apparent conflict between the selectivity and speed of transport.nuclear pore | molecular dynamics | nucleoporins | transport factors | NMR T he nuclear pore complex (NPC) regulates macromolecular transport between the nucleus and the cytoplasm in all eukaryotic cells (1, 2). The NPC allows for passive diffusion of small molecules including sugars, ions, and water, while simultaneously imposing size-dependent exclusion of macromolecules without nuclear transport factor (TF) binding sites, generating unique nuclear and cytoplasmic compartments (3, 4). Larger macromolecules can bypass the selectivity barrier of the NPC by interacting with TFs that shuttle cargo through the central channel of the pore. In pathological conditions, including many cancers and viral infections, the NPC is hijacked and used to transport undesired particles, or it is modified to attenuate the cellular responses to disease onset (5, 6).TFs traverse the NPC by selective and reversible association with disordered phenylalanine-glycine (FG) repeat domains of the FG nucleoporin proteins (FG Nups), which line the surface of the NPC (7-14). Each FG repeat domain consists of 5-50 FG repeats. In turn, each FG repeat consists of a single FG motif of various sequence flavors, such as the FSFG and GLFG motifs, and 10-30 spacer residues that separate consecutive FG motifs (15, 16). The spacer residues are strongly hydrophilic (17) and rich ...

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“…A variety of simulation methods (MD, Monte Carlo, metadynamics, replica exchange) and different levels of representation (coarse-grained, implicit solvent, all-atom with explicit water) have been used to obtain IDP ensembles. 7,[21][22][23][24][25][26][27][28][29] There are two main challenges encountered in de novo simulations.…”

Section: Introductionmentioning

confidence: 99%

“…On the one hand, good agreement between computed and measured experimental observables was observed in some IDP simulations. [23][24][25]27,28,42,[44][45][46] On the other hand, the accuracy of unfolded state and IDP structural ensembles obtained using several widely-used force fields has been called into question. [25][26][27]43,[46][47][48][49][50][51][52][53] Piana et al suggested that modern force fields, including Amber ff99sb*-ildn and CHARMM 22* in particular, produce IDP and unfolded state ensembles that are on average too compact.…”

Section: Introductionmentioning

confidence: 99%

Structural Ensembles of Intrinsically Disordered Proteins Depend Strongly on Force Field: A Comparison to Experiment

Rauscher

Gapsys

Gajda

et al. 2015

J. Chem. Theory Comput.

412

447

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Intrinsically disordered proteins (IDPs) are notoriously challenging to study both experimentally and computationally. The structure of IDPs cannot be described by a single conformation but must instead be described as an ensemble of interconverting conformations. Atomistic simulations are increasingly used to obtain such IDP conformational ensembles. Here, we have compared the IDP ensembles generated by eight all-atom empirical force fields against primary small-angle X-ray scattering (SAXS) and NMR data. Ensembles obtained with different force fields exhibit marked differences in chain dimensions, hydrogen bonding, and secondary structure content. These differences are unexpectedly large: changing the force field is found to have a stronger effect on secondary structure content than changing the entire peptide sequence. The CHARMM 22* ensemble performs best in this force field comparison: it has the lowest error in chemical shifts and J-couplings and agrees well with the SAXS data. A high population of left-handed α-helix is present in the CHARMM 36 ensemble, which is inconsistent with measured scalar couplings. To eliminate inadequate sampling as a reason for differences between force fields, extensive simulations were carried out (0.964 ms in total); the remaining small sampling uncertainty is shown to be much smaller than the observed differences. Our findings highlight how IDPs, with their rugged energy landscapes, are highly sensitive test systems that are capable of revealing force field deficiencies and, therefore, contributing to force field development.

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Disordered Structural Ensembles of Vasopressin and Oxytocin and Their Mutants

Cited by 34 publications

References 54 publications

Oxytocin and arginine vasopressin receptor evolution: implications for adaptive novelties in placental mammals

Oxytocin and arginine vasopressin receptor evolution: implications for adaptive novelties in placental mammals

Slide-and-exchange mechanism for rapid and selective transport through the nuclear pore complex

Structural Ensembles of Intrinsically Disordered Proteins Depend Strongly on Force Field: A Comparison to Experiment

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