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Peter J. Implementation and testing of stable, fast implicit solvation in molecular dynamics using the smooth-permittivity finite difference Poisson-Boltzmann method.


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Implicit solvation based on generalized Born theory in different dielectric environments. Recent advances in the development. Feig , C. Brooks , III. Related Papers. By clicking accept or continuing to use the site, you agree to the terms outlined in our Privacy Policy , Terms of Service , and Dataset License. The electron density in the Y66F active mutant suggests that both the active and flipped substrate conformers as well as two Arg 72 conformers are present fig. S3A , but disorder prevented firmer interpretation.

Since no plausible amino acid is positioned to directly remove the proton from the amide, we considered disruption of conjugation akin to N-linked glycosyl transferase 15 , in which two strong hydrogen bonds thus requiring a primary amide are made to Asn, but the OphA structure does not support this mechanism. Both Tyr 66 and Tyr 76 are, however, well positioned to stabilize the resulting tetrahedral carbon by hydrogen bonding. However, it is 5.

Peptide Solvation and H-bonds, Volume 72

We also considered whether a water molecule could perform this attack and form a geminal diol intermediate. The reaction in the presence of H 2 18 O shows no 18 O incorporation in the peptide, and the structure shows no water or base appropriately positioned for this reaction, arguing against such a mechanism. Further, a geminal diol intermediate would be predicted to give rise to peptide bond cleavage at the very least as an otherwise unwanted side reaction, which was not observed. Finally, formation of a tetrahedral intermediate would seem inconsistent with the observed decreased methylation rate kinetic isotope effect of 3 in vitro in D 2 O fig.

Since it was not possible to obtain a fully occupied SAM complex with any active protein, we used sinefungin fig. S3B , consistent with the electron density Fig. S3A of the cofactors, and thus, these structures are substrate complex mimics. We conclude that the extensive hydrogen-bonding network at the active site and the catenane-like arrangement lead to a highly rigid active site.

In both sinefungin complexes, the two nitrogen atoms sinefungin and amide approach close enough to form a hydrogen bond distance varies between 3. Using structural superposition, we noted that placing in silico the larger SAM molecule into the SAH complex places the methyl group approximately 2.

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This clash is likely the reason why we have been unable to obtain fully occupied SAM complexes with active proteins. Although close contacts have been observed between SAM and its substrate in a number of structures 22 — 25 , OphA appears to have the shortest distance.

The HPLC analysis in fig. S3B shows some residual SAH remains.

Carbon atoms are shown in yellow, sulfur in dark yellow, oxygen in red, and nitrogen in blue. The same color scheme and perspective as in Fig. The arrangement of atoms is consistent with the S N 2 attack by the amide on the cofactor. E The inactive mutant R72A-SAM complex, where the anchoring interactions between substrate and enzyme are disrupted, avoids this steric clash.

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The enzyme does not significantly rearrange to tolerate this change in substrate conformation. We therefore hypothesize that, by disrupting anchoring interactions, the flipped conformation can be adopted to relieve the steric clashes between SAM and the amide that would otherwise occur Fig. QM calculations show that deprotonation of the amide must occur prior to S N 2 attack fig. S8 ; notably, the educt is higher in energy than the intermediate due to the steric clash between SAM and the substrate. In all crystal structures, a water molecule, hydrogen-bonded to the amine of cofactor, is conserved 5.

Calculations show that water can function as the base Figs. This process is similar to the base-catalyzed proton exchange of amides occurring in proteins at moderate pH The hydrogen-bonding network of the water may enhance its basicity Figs. The resulting negatively charged oxygen of the imidate would be stabilized by hydrogen bonds to Tyr 66 and Tyr A barrier of 5. Water molecules observed in the MD simulation were considered.

SAM is shown in yellow, the substrate in cyan, and key residues in the binding pocket in pink.

Apolar hydrogens are omitted for clarity. B Energy profile of the proposed two-step reaction obtained from the QM calculations. QM calculations require a defined location of the proton in the intermediate state for convergence. The deprotonated carboxyl group of SAM was used as the ultimate destination; however, other routes are plausible. Perfect S N 2 alignment of the methyl group of SAM was not observed in the model system and level of theory used.


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A The conserved water molecule acts as base to remove the proton from the substrate to generate the imidate. Purchase Instant Access. View Preview. Learn more Check out. Related Information. Close Figure Viewer. Browse All Figures Return to Figure. Previous Figure Next Figure. Email or Customer ID. Forgot password? Old Password. New Password. Password Changed Successfully Your password has been changed.

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