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Combinatorial Approach for Exploring Conformational Space and Activation Barriers in Computer-Aided Enzyme Design.

ABSTRACT: Computer-aided enzyme design is a field of great potential importance for biotechnological applications, medical advances, and a fundamental understanding of enzyme action. However, reaching a predictive ability in this direction is extremely challenging. It requires both the ability to predict quantitatively the activation barriers in cases where the structure and sequence are known and the ability to predict the effect of different mutations. In this work, we propose a protocol for predicting reasonable starting structures of mutants of proteins with known structures and for calculating the activation barriers of the generated mutants. Our approach also allows us to use the predicted structures of the generated mutant to predict structures and activation barriers for subsequent set of mutations. This protocol is used to examine the reliability of the in silico directed evolution of Kemp eliminase and haloalkane dehalogenase. We also used the results of single and double mutations as a base for predicting the effect of transition-state stabilization by multiple concurrent mutations. This strategy seems to be useful in creating an activity funnel that provides a qualitative ranking of the catalytic power of different mutants.

SUBMITTER: Mondal D

PROVIDER: S-EPMC8225234 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe premature loss of primary teeth is a common problem in pediatric dentistry, resulting in disruption of the arch integrity. Hence, space maintainers (SM) used for maintaining spaces are necessary. However, current methods of making removable space maintainers (RSM) have some limitations.MethodsDigital models of dentition defects were obtained by using a scanning technique coupled with laser medical image reconstruction. The digital RSMs were designed using the 3Shape software. They were manufactured using two methods: polyetheretherketone (PEEK), and conventional methods (20 RSMs per group). For qualitative evaluation, the Likert five-point scale was used by 10 experts to obtain a score for 40 RSMs. The spaces between the tissue surfaces of the RSMs and the models were replaced using silicone, and the maximum and mean distances, as well as the standard deviation, were measured. A three-dimensional variation analysis was used to measure these spaces. The student's t-test and Satterthwaite t-test were used to compare the differences in the spaces for the various materials.ResultsThe PEEK RSMs were found to fit the models well. In the qualitative assessment, the mean experts' scores for the PEEK and conventional groups were 1.80 ± 0.40 and 1.82 ± 0.40, and there was no significant difference between the two groups (p = 0.875). In the quantitative assessment, the mean spaces for the PEEK digital RSMs and the conventional RSMs were 44.32 ± 1.75 μm, and 137.36 ± 18.63 μm, respectively, and the differences were statistically significant (p < 0.001). In addition, there were significant differences in the maximum space and the standard deviation between the two groups.ConclusionDigitally designed and integrated RSMs were found to be superior to those produced using the conventional method. 3D variation analysis results showed that the mean distances and standard deviations of the PEEK groups were significantly smaller than those of conventional group (p < 0.01). A PEEK-manufactured RSM produced using CAD/CAM would be extremely suitable for clinical applications.

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Combinatorial Approach for Exploring Conformational Space and Activation Barriers in Computer-Aided Enzyme Design.

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