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Substrate entropy in enzyme enantioselectivity: An experimental and molecular modeling study of a lipase
Author(s) -
Ottosson Jenny,
Fransson Linda,
Hult Karl
Publication year - 2002
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.3480102
Subject(s) - chemistry , enthalpy , lipase , butanol , enantiomer , stereochemistry , entropy (arrow of time) , thermodynamics , organic chemistry , enzyme , physics , ethanol
The temperature dependence of the enantioselectivity of Candida antarctica lipase B for 3‐hexanol, 2‐butanol, 3‐methyl‐2‐butanol, 3,3‐dimethyl‐2‐butanol, and 1‐bromo‐2‐butanol revealed that the differential activation entropy, Δ R−S Δ S ‡ , was as significant as the differential activation enthalpy, Δ R−S Δ H ‡ , to the enantiomeric ratio, E. 1‐Bromo‐2‐butanol, with isosteric substituents, displayed the largest Δ R−S Δ S ‡ . 3‐Hexanol displayed, contrary to other sec ‐alcohols, a positive Δ R−S Δ S ‡ . In other words, for 3‐hexanol the preferred R ‐enantiomer is not only favored by enthalpy but also by entropy. Molecular dynamics (MD) simulations and systematic search calculations of the substrate accessible volume within the active site revealed that the ( R )‐3‐hexanol transition state (TS) accessed a larger volume within the active site than the ( S )‐3‐hexanol TS. This correlates well with the higher TS entropy of ( R )‐3‐hexanol. In addition, this enantiomer did also yield a higher number of allowed conformations, N, from the systematic search routines, than did the S ‐enantiomer. The substrate accessible volume was greater for the enantiomer preferred by entropy also for 2‐butanol. For 3,3‐dimethyl‐2‐butanol, however, neither MD‐simulations nor systematic search calculations yielded substrate accessible volumes that correlate to TS entropy. Ambiguous results were achieved for 3‐methyl‐2‐butanol.