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Simulating the fidelity and the three Mg mechanism of pol ? and clarifying the validity of transition state theory in enzyme catalysis.

ABSTRACT: Pol ? belongs to the important Y family of DNA polymerases that can catalyze translesion synthesis across sites of damaged DNA. This activity involves the reduced fidelity of Pol ? for 8-oxo-7,8-dhyedro-2'-deoxoguanosin(8-oxoG). The fundamental interest in Pol ? has grown recently with the demonstration of the importance of a 3rd Mg2+ ion. The current work explores both the fidelity of Pol ? and the role of the 3rd metal ion, by using empirical valence bond (EVB) simulations. The simulations reproduce the observed trend in fidelity and shed a new light on the role of the 3rd metal ion. It is found that this ion does not lead to a major catalytic effect, but most probably plays an important role in reducing the product release barrier. Furthermore, it is concluded, in contrast to some implications, that the effect of this metal does not violate transition state theory, and the evaluation of the catalytic effect must conserve the molecular composition upon moving from the reactant to the transition state. Proteins 2017; 85:1446-1453. © 2017 Wiley Periodicals, Inc.

SUBMITTER: Yoon H

PROVIDER: S-EPMC5531179 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Simulating the fidelity and the three Mg mechanism of pol η and clarifying the validity of transition state theory in enzyme catalysis.

Yoon Hanwool H Warshel Arieh A

Proteins 20170504 8

Pol η belongs to the important Y family of DNA polymerases that can catalyze translesion synthesis across sites of damaged DNA. This activity involves the reduced fidelity of Pol η for 8-oxo-7,8-dhyedro-2'-deoxoguanosin(8-oxoG). The fundamental interest in Pol η has grown recently with the demonstration of the importance of a 3rd Mg2+ ion. The current work explores both the fidelity of Pol η and the role of the 3rd metal ion, by using empirical valence bond (EVB) simulations. The simulations rep ...[more]

PMID: 28383109

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Project description:In accordance with the physiological networks that underlie it, human cognition is characterized by both the segregation and interdependence of a number of cognitive domains. Cognition itself, therefore, can be conceptualized as a network of functions. A network approach to cognition has previously revealed topological differences in cognitive profiles between healthy and disease populations. The present study, therefore, used graph theory to determine variation in cognitive profiles across healthy aging and cognitive impairment. A comprehensive neuropsychological test battery was administered to 415 participants. This included three groups of healthy adults aged 18-39 (n = 75), 40-64 (n = 75), and 65 and over (n = 70) and three patient groups with either amnestic (n = 75) or non-amnestic (n = 60) mild cognitive impairment or Alzheimer's type dementia (n = 60). For each group, cognitive networks were created reflective of test-to-test covariance, in which nodes represented cognitive tests and edges reflected statistical inter-nodal significance (p < 0.05). Network metrics were derived using the Brain Connectivity Toolbox. Network-wide clustering, local efficiency and global efficiency of nodes showed linear differences across the stages of aging, being significantly higher among older adults when compared with younger groups. Among patients, these metrics were significantly higher again when compared with healthy older controls. Conversely, average betweenness centralities were highest in middle-aged participants and lower among older adults and patients. In particular, compared with controls, patients demonstrated a distinct lack of centrality in the domains of semantic processing and abstract reasoning. Network composition in the amnestic mild cognitive impairment group was similar to the network of Alzheimer's dementia patients. Using graph theoretical methods, this study demonstrates that the composition of cognitive networks may be measurably altered by the aging process and differentially impacted by pathological cognitive impairment. Network alterations characteristic of Alzheimer's disease in particular may occur early and be distinct from alterations associated with differing types of cognitive impairment. A shift in centrality between domains may be particularly relevant in identifying cognitive profiles indicative of underlying disease. Such techniques may contribute to the future development of more sophisticated diagnostic tools for neurodegenerative disease.

Dataset Information

Simulating the fidelity and the three Mg mechanism of pol ? and clarifying the validity of transition state theory in enzyme catalysis.

Publications

Simulating the fidelity and the three Mg mechanism of pol η and clarifying the validity of transition state theory in enzyme catalysis.

Similar Datasets

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