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On catalytic preorganization in oxyanion holes: highlighting the problems with the gas-phase modeling of oxyanion holes and illustrating the need for complete enzyme models.

ABSTRACT: Oxyanion holes play a major role in catalyzing enzymatic reactions, yet the corresponding energetics is frequently misunderstood. The main problem may be associated with the nontrivial nature of the electrostatic preorganization effect, without following the relevant formulation. That is, although the energetics of oxyanion holes have been fully quantified in early studies (which include both the enzymatic and reference solution reactions), the findings of these studies are sometimes overlooked, and, in some cases, it is assumed that gas-phase calculations with a fixed model of an oxyanion hole are sufficient for assessing the corresponding effect in the protein. Herein, we present a systematic analysis of this issue, clarifying the problems associated with modeling oxyanions by means of two fixed water molecules (or related constructs). We then re-emphasize the point that the effect of the oxyanion hole is mainly due to the fact that the relevant dipoles are already set in an orientation that stabilizes the TS charges, whereas the corresponding dipoles in solution are randomly oriented, resulting in the need to pay a very large reorganization energy. Simply calculating interaction energies with relatively fixed species cannot capture this crucial point, and considering it may help in advancing rational enzyme design.

SUBMITTER: Kamerlin SC

PROVIDER: S-EPMC2945449 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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On catalytic preorganization in oxyanion holes: highlighting the problems with the gas-phase modeling of oxyanion holes and illustrating the need for complete enzyme models.

Kamerlin Shina C L SC Chu Zhen T ZT Warshel A A

The Journal of organic chemistry 20101001 19

Oxyanion holes play a major role in catalyzing enzymatic reactions, yet the corresponding energetics is frequently misunderstood. The main problem may be associated with the nontrivial nature of the electrostatic preorganization effect, without following the relevant formulation. That is, although the energetics of oxyanion holes have been fully quantified in early studies (which include both the enzymatic and reference solution reactions), the findings of these studies are sometimes overlooked, ...[more]

PMID: 20825150

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Project description:BACKGROUND:The Choosing Wisely campaign has spread to many countries. Methods for developing recommendations are inconsistent. We describe our process of developing such recommendations from a comprehensive national set of clinical practice guidelines (Current Care, CC) and the results of a one-year Choosing Wisely Finland project. METHODS:Two of the authors drafted the quality and process criteria for all the Choosing Wisely Finland recommendations. The quality criteria were relevance, feasibility, evidence-based and strength. These were discussed in editors' meetings and subsequently revised. Two different processes for developing recommendations within national clinical practice guidelines were designed and piloted (processes A and B). Process A was based on a published guideline. The recommendations are drafted by an editor and revised and approved by the guideline development group. In process B the development of the recommendations is integrated with guideline production or update. Choosing Wisely recommendations were then drafted for half of the published CC Guidelines. An additional process (process C) was designed for producing independent recommendations outside a guideline. RESULTS:At least one Choosing Wisely recommendation could be identified from 39 out of 52 reviewed guidelines. Of the 106 recommendations drafted, 62 (58%) were accepted for publication. The main reasons for rejection were inability to give a strong recommendation (n?=?18, 41%) and insufficient relevance (n?=?14, 32%). Two thirds (n?=?41, 66%) of the published recommendations were based on high to moderate level of evidence, and 18% (n?=?11) on low or very low level of evidence, whereas for the rest, the quality of evidence was not critically appraised. CONCLUSIONS:Choosing Wisely recommendations can be produced systematically from existing clinical practice guidelines. The rigorous methods of evidence-based medicine ensure high-quality recommendations. We welcome the use of our processes and methods describes in this article by other guideline-producing organizations.

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On catalytic preorganization in oxyanion holes: highlighting the problems with the gas-phase modeling of oxyanion holes and illustrating the need for complete enzyme models.

Publications

On catalytic preorganization in oxyanion holes: highlighting the problems with the gas-phase modeling of oxyanion holes and illustrating the need for complete enzyme models.

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