uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Transition States in a Protein Environment: ONIOM QM:MM Modeling of Isopenicillin N Synthesis
Kyoto Univ, Fukui Inst Fundamental Chem, Sakyo Ku, Kyoto 6068103, Japan.ORCID iD: 0000-0002-1312-1202
Kyoto Univ, Fukui Inst Fundamental Chem, Sakyo Ku, Kyoto 6068103, Japan.
Gaussian Inc, Wallingford, CT 06492 USA.
Gaussian Inc, Wallingford, CT 06492 USA.
Show others and affiliations
2009 (English)In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 5, no 1, 222-234 p.Article in journal (Refereed) Published
Abstract [en]

To highlight the role of the protein in metal enzyme catalysis, we optimize ONIOM QM:MM transition states and intermediates for the full reaction of the nonheme iron enzyme isopenicillin N synthase (IPNS). Optimizations of transition states in large protein systems are possible using our new geometry optimizer with quadratic coupling between the QM and MM regions [Vreven, T. et al. MoL Phys. 2006, 104, 701-704]. To highlight the effect of the metal center, results from the protein model are compared to results from an active site model containing only the metal center and coordinating residues [Lundberg, M. et al. Biochemistry 2008, 47, 1031-10421. The analysis suggests that the main catalytic effect comes from the metal center, while the protein controls the reactivity to achieve high product specificity. As an example, hydrophobic residues align the valine substrate radical in a favorable conformation for thiazolicline ring closure and contribute to product selectivity and high stereospecificity. A low-barrier pathway for P-lactam formation is found where the proton required for heterolytic O-O bond cleavage comes directly from the valine N-H group of the substrate. The alternative mechanism, where the proton in 0-0 bond cleavage initially comes from an iron water ligand, can be disfavored by the electrostatic interactions with the surrounding protein. Explicit protein effects on transition states are typically 1-6 kcal/mol in the present enzyme and can be understood by considering whether the transition state involves large movements of the substrate as well as whether it involves electron transfer.

Place, publisher, year, edition, pages
2009. Vol. 5, no 1, 222-234 p.
National Category
Physical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-145465DOI: 10.1021/ct800457gISI: 000262432000024PubMedID: 26609836OAI: oai:DiVA.org:uu-145465DiVA: diva2:396516
Available from: 2011-02-10 Created: 2011-02-09 Last updated: 2017-12-11Bibliographically approved

Open Access in DiVA

fulltext(7673 kB)116 downloads
File information
File name FULLTEXT01.pdfFile size 7673 kBChecksum SHA-512
786afce11e47bb154bff2a93ed1c42e37ae5006c59942e6e7da367987f97022bc94ab4084073674c04f911cf7a2dcec90e811576db454ea4506fffbfb54e7f47
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Authority records BETA

Lundberg, Marcus

Search in DiVA

By author/editor
Lundberg, Marcus
In the same journal
Journal of Chemical Theory and Computation
Physical Chemistry

Search outside of DiVA

GoogleGoogle Scholar
Total: 116 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 825 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf