Browsing by Author "Barnett, Christopher B"

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    Interpreting medium ring canonical conformers by a triangular plane tessellation of the macrocycle
    (AIP Publishing, 2013) Khalili, Pegah; Barnett, Christopher B; Naidoo, Kevin J
    Cyclic conformational coordinates are essential for the distinction of molecular ring conformers as the use of Cremer-Pople coordinates have illustrated for five- and six-membered rings. Here, by tessellating medium rings into triangular planes and using the relative angles made between triangular planes we are able to assign macrocyclic pucker conformations into canonical pucker conformers such as chairs, boats, etc. We show that the definition is straightforward compared with other methods popularly used for small rings and that it is computationally simple to implement for complex macrocyclic rings. These cyclic conformational coordinates directly couple to the motion of individual nodes of a ring. Therefore, they are useful for correlating the physical properties of macrocycles with their ring pucker and measuring the dynamic ring conformational behavior. We illustrate the triangular tessellation, assignment, and pucker analysis on 7- and 8-membered rings. Sets of canonical states are given for cycloheptane and cyclooctane that have been previously experimentally analysed.
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    Molecular details from computational reaction dynamics for the cellobiohydrolase I glycosylation reaction
    (American Chemical Society, 2011) Barnett, Christopher B; Wilkinson, Karl A; Naidoo, Kevin J
    Glycosylation of cellobiose hydrolase I (CBHI), is a key step in the processing and degradation of cellulose. Here the pathways and barriers of the reaction are explored using the free energy from adaptive reaction coordinate forces (FEARCF) reaction dynamics method coupled with SCC-DFTB/MM. In many respects CBHI follows the expected general GH7 family mechanism that involves the Glu-X-Asp-X-X-Glu motif. However, critical electronic and conformational details, previously not known, were discovered through our computations. The central feature that ensures the success of the glycosylation reaction are the Glu212 nucleophile’s hydrogen bond to the hydroxyl on C2, of the glucose in the −1 position of the cellulosic strand. This Glu212 function restricts the C2 hydroxyl in such a way as to favor the formation of the 4E ring pucker of the −1 position glucose. A frontier molecular orbital analysis of the structures along the reaction surface proves the existence of an oxocarbenium ion, which has both transition state and intermediate character. The transition state structure is able to descend down the glycosylation pathway through the critical combination of Asp214 (HOMO), ring oxygen (LUMO), and Glu212 (HOMO), anomeric carbon (LUMO) interactions. Using the fully converged FEARCF SCC-DFTB/MM reaction surface, we find a barrier of 17.48 kcal/mol separating bound cellulose chain from the glycosylated CBHI. Taking recrossing into account gives kcat = 0.415 s–1 for cellobiohydrolase glycosylation.
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    Molecular details from computational reaction dynamics for the cellobiohydrolase I glycosylation reaction
    (American Chemical Society, 2011) Barnett, Christopher B; Wilkinson, Karl A; Naidoo, Kevin J
    Glycosylation of cellobiose hydrolase I (CBHI), is a key step in the processing and degradation of cellulose. Here the pathways and barriers of the reaction are explored using the free energy from adaptive reaction coordinate forces (FEARCF) reaction dynamics method coupled with SCC-DFTB/MM. In many respects CBHI follows the expected general GH7 family mechanism that involves the Glu-X-Asp-X-X-Glu motif. However, critical electronic and conformational details, previously not known, were discovered through our computations. The central feature that ensures the success of the glycosylation reaction are the Glu212 nucleophile’s hydrogen bond to the hydroxyl on C2, of the glucose in the −1 position of the cellulosic strand. This Glu212 function restricts the C2 hydroxyl in such a way as to favor the formation of the 4E ring pucker of the −1 position glucose. A frontier molecular orbital analysis of the structures along the reaction surface proves the existence of an oxocarbenium ion, which has both transition state and intermediate character. The transition state structure is able to descend down the glycosylation pathway through the critical combination of Asp214 (HOMO), ring oxygen (LUMO), and Glu212 (HOMO), anomeric carbon (LUMO) interactions. Using the fully converged FEARCF SCC-DFTB/MM reaction surface, we find a barrier of 17.48 kcal/mol separating bound cellulose chain from the glycosylated CBHI. Taking recrossing into account gives kcat = 0.415 s–1 for cellobiohydrolase glycosylation.
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    PNP Diminishes Guanosine Glycosidic Bond Strength Through Restrictive Ring Pucker as a Precursor to Phosphorylation
    (The Journal of Physical Chemistry, 2013) Barnett, Christopher B; Naidoo, Kevin J
    Purine nucleoside phosphorylase is a transferase that catalyzes the addition of phosphate and removal of a purine base from guanosine and similar nucleosides. Here the interplay between sugar puckering conformation, the enzyme, and the perceived course of the reaction is examined using QM/MM FEARCF dynamics simulations. The enzyme biases the guanosine sugar ring toward a flattened 4E conformer as a step that is critical to the success of the phosphorylation reaction. The C4′ endo conformer allows the nonbonded ring oxygen orbital to align and donate electrons into the antibonding glycosidic bond orbital, thus weakening the bond. This conformational preference is due to sustained and directed noncovalent interactions anchored by the phosphate nucleophile’s hydrogen bonds to the sugar C2′ and C3′ hydroxyls. In so doing, PNP alters the solution sugar ring pucker preferences as part of its catalytic reaction barrier lowering function.