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Ribozyme catalysis with a twist: active state of the twister ribozyme in solution predicted from molecular simulation

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TypeOfResource
Text
TitleInfo
Title
Ribozyme catalysis with a twist: active state of the twister ribozyme in solution predicted from molecular simulation
Name (type = personal)
NamePart (type = family)
Gaines
NamePart (type = given)
Colin S.
Affiliation
Proteomics, Rutgers University
Role
RoleTerm (type = text); (authority = marcrt)
author
Name (type = personal)
NamePart (type = family)
York
NamePart (type = given)
Darrin M.
Affiliation
Proteomics, Rutgers University
Role
RoleTerm (type = text); (authority = marcrt)
author
Name (type = corporate); (authority = RutgersOrg-Department)
NamePart
Proteomics
Genre (authority = RULIB-FS)
Article, Refereed
Genre (authority = NISO JAV)
Accepted Manuscript (AM)
Note (type = peerReview)
Peer reviewed
OriginInfo
DateCreated (encoding = w3cdtf); (qualifier = exact); (keyDate = yes)
2016
Abstract (type = Abstract)
We present results from molecular dynamics simulations and free energy calculations of the twister ribozyme at different stages along the reaction path to gain insight into its mechanism. The results, together with recent biochemical experiments, provide support for a mechanism involving general-acid catalysis by a conserved adenine residue in the active site. Although adenine has been previously implicated as a general acid acting through the N1 position in other ribozymes such as the hairpin and VS ribozymes, in the twister ribozyme there may be a twist. Biochemical experiments suggest that general acid catalysis may occur through the N3 position, which has never before been implicated in this role; however, currently, there is a lack of a detailed structural model for the active state of the twister ribozyme in solution that is consistent with these and other experiments. Simulations in a crystalline environment reported here are consistent with X-ray crystallographic data, and suggest that crystal packing contacts trap the RNA in an inactive conformation with U-1 in an extruded state that is incompatible with an in-line attack to the scissile phosphate. Simulations in solution, on the other hand, reveal this region to be dynamic and able to adopt a conformation where U-1 is stacked with G33. In this state, the nucleophile is in line with the scissile phosphate, and the N1 position of G33 and N3 position of A1 are poised to act as a general base and acid, respectively, as supported by mutational experiments. Free energy calculations further predict the electrostatic environment causes a shift of the microscopic pKa at the N3 position of A1 toward neutrality by approximately 5 pKa units. These results offer a unified interpretation of a broad range of currently available experimental data that points to a novel mode of general acid catalysis through the N3 position of an adenine nucleobase, thus expanding the repertoire of known mechanistic strategies employed by small nucleolytic ribozymes.
Language
LanguageTerm (authority = ISO 639-3:2007); (type = text)
English
PhysicalDescription
InternetMediaType
application/pdf
Extent
1 online resource (23 pages) : illustrations
Subject (authority = local)
Topic
Twister ribozyme
Subject (authority = local)
Topic
Molecular dynamics
Subject (authority = local)
Topic
RNA
Extension
DescriptiveEvent
Type
Citation
DateTime (encoding = w3cdtf)
2016
AssociatedObject
Name
Journal of the American Chemical Society
Type
Journal
Relationship
Has part
Detail
3058-3065
Identifier (type = volume and issue)
138(9)
Reference (type = url)
https://doi.org/10.1021/jacs.5b12061
Extension
DescriptiveEvent
Type
Grant award
AssociatedEntity
Role
Funder
Name
National Institutes of Health
AssociatedEntity
Role
Originator
Name
Darrin York
AssociatedObject
Type
Grant number
Name
GM62248
RelatedItem (type = host)
TitleInfo
Title
Gaines, Colin S.
Identifier (type = local)
rucore30196900001
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier (type = doi)
doi:10.7282/T31C1ZX8
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Copyright for scholarly resources published in RUcore is retained by the copyright holder. By virtue of its appearance in this open access medium, you are free to use this resource, with proper attribution, in educational and other non-commercial settings. Other uses, such as reproduction or republication, may require the permission of the copyright holder.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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Type
Permission or license
AssociatedObject
Type
License
Name
Multiple author license v. 1
Detail
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