Impact of Cl? and Na+ ions on simulated structure and dynamics of ?ARK1 PH domain

Pfeiffer, Stefania; Fushman, David; Cowburn, David

doi:10.1002/(sici)1097-0134(19990501)35:2<206::aid-prot7>3.0.co;2-a

Cited by 28 publications

(36 citation statements)

References 49 publications

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“…Simulations of other constructs were performed by modification of this starting system. Systems were equilibrated using standard equilibration protocols (41,81,82) in AMBER (83,84). Long timescale simulations were conducted on the Anton system with a 2-fs time step (85).…”

Section: Methodssupporting

confidence: 88%

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.

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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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Section: Methodssupporting

confidence: 88%

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.

Self Cite

131

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“…60 Yet and , the RDF capture the interactions between ions and protein backbone and side-chains and have been used to characterize the attraction between ions and the protein surface. 18,30,[61][62][63] To make sure that the attraction of ions to the protein surface is not a geometrical Analysis of the X-ray coordinates of alkali metal ions and halides bound to proteins was carried out by using the PDBeMotif search tool 53 ( Figure 5). Alkali metal ions bind preferentially to side chains of glu and asp residues, and less often to polar residues such as ser, asn or thr.…”

Section: Gross Interactions Between the Protein And The Ionsmentioning

confidence: 99%

Ions and the Protein Surface Revisited: Extensive Molecular Dynamics Simulations and Analysis of Protein Structures in Alkali-Chloride Solutions

Friedman

2011

J. Phys. Chem. B

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Proteins interact with ions in various ways. The surface of proteins has an innate capability to bind ions, and is also influenced by the screening of the electrostatic potential owing to the presence of salts in the bulk solution. Alkali metal ions and chlorides interact with the protein surface, but such interactions are relatively weak and often transient. In this paper, computer simulations and analysis of protein structures are used to characterize the interactions between ions and the protein surface. The results show that the ion-binding properties of protein residues are highly variable. For example, alkali metal ions are more often associated with aspartate residues than with glutamates, whereas chlorides are most likely to be located near arginines. When comparing NaCl and KCl solutions, it was found that certain surface residues attract the anion more strongly in NaCl. This study demonstrates that proteinsalt interactions should be accounted for in the planning and execution of experiments and simulations involving proteins, particularly if subtle structural details are sought after.

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“…The addition of explicit salt ions (more than charge-balancing counter ions) to near-physiological conditions is required for reducing artifacts on the peptide conformation during the simulations. 25,26 For the mixed lipid bilayer system, 14 Na + as counter ions are inserted to neutralize the system (the system contains 6 positively charged residues and 20 anionic lipids). 16 Na + and 16 Cl -are also added to get the same salt concentration.…”

Section: Methodsmentioning

confidence: 99%

Computational Study of Cytolytic Peptides: Monomeric-Oligomeric Structures and Ligand Interactions

Ma¹,

Nussinov²

2005

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY) SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTWe have mostly followed our initial plan described in the Statement of Work to investigate membrane disrupting peptide dynamics and membrane interactions. In the first year of research, we have focused on two systems (Protegrin-1, β−Defensin). The major progresses have been made in PG-1 membrane interactions, and the β−defensin oligomerization also has preceded well. The important scientific finding during the research period is the elucidation of peptide membrane thinning mechanism. We observed that local thinning of lipid bilayers mediated by the peptide is enhanced in the lipid bilayer containing POPG, consistent with experimental results of selective membrane targeting. The conformational dynamics of Protegrin-1, especially the highly charged β-hairpin turn region are found to be mostly responsible for disturbing membrane. Even though the eventual membrane disruption requires Protegrin-1 oligomer, our simulations clearly show the first step of the monomeric effects. The thinning effects in the bilayer should relate to pore/channel formation in lipid bilayer and thus responsible for further defects in the membrane caused by oligomer. These results reveal first time how a peptide in β-hairpin conformation (rather than conventional α-helical structure) can disrupt membrane structure. SUBJECT TERMSMembrane-damaging, pore-forming, β-sheet, toxin, protegrin, antimicrobials, antibiotic

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Impact of Cl? and Na+ ions on simulated structure and dynamics of ?ARK1 PH domain

Cited by 28 publications

References 49 publications

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

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

Ions and the Protein Surface Revisited: Extensive Molecular Dynamics Simulations and Analysis of Protein Structures in Alkali-Chloride Solutions

Computational Study of Cytolytic Peptides: Monomeric-Oligomeric Structures and Ligand Interactions

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