10.1021/ja209650h.s001
Yue Yang
Yue
Yang
Bing Wang
Bing
Wang
Melek
N. Ucisik
Melek
N.
Ucisik
Guanglei Cui
Guanglei
Cui
Carol A. Fierke
Carol A.
Fierke
Kenneth M. Merz
Kenneth M.
Merz
Insights into the Mechanistic
Dichotomy of the Protein
Farnesyltransferase Peptide Substrates CVIM and CVLS
American Chemical Society
2012
peptide substrates
umbrella sampling techniques
SN 2 TS
isotope
CVLS
SKIE
FTase
absence
transition state structure
Protein Farnesyltransferase Peptide Substrates CVIM
2012-01-18 00:00:00
Media
https://acs.figshare.com/articles/media/Insights_into_the_Mechanistic_Dichotomy_of_the_Protein_Farnesyltransferase_Peptide_Substrates_CVIM_and_CVLS/2558770
Protein farnesyltransferase (FTase) catalyzes farnesylation
of
a variety of peptide substrates. <sup>3</sup>H α-secondary kinetic
isotope effect (α-SKIE) measurements of two peptide substrates,
CVIM and CVLS, are significantly different and have been proposed
to reflect a rate-limiting S<sub>N</sub>2-like transition state with
dissociative characteristics for CVIM, while, due to the absence of
an isotope effect, CVLS was proposed to have a rate-limiting peptide
conformational change. Potential of mean force quantum mechanical/molecular
mechanical studies coupled with umbrella sampling techniques were
performed to further probe this mechanistic dichotomy. We observe
the experimentally proposed transition state (TS) for CVIM but find
that CVLS has a symmetric S<sub>N</sub>2 TS, which is also consistent
with the absence of a <sup>3</sup>H α-SKIE. These calculations
demonstrate facile substrate-dependent alterations in the transition
state structure catalyzed by FTase.