Dataset Information

A case study comparing quantitative stability-flexibility relationships across five metallo-?-lactamases highlighting differences within NDM-1.

ABSTRACT: The Distance Constraint Model (DCM) is an ensemble-based biophysical model that integrates thermodynamic and mechanical viewpoints of protein structure. The DCM outputs a large number of structural characterizations that collectively allow for Quantified Stability-Flexibility Relationships (QSFR) to be identified and compared across protein families. Using five metallo-?-lactamases (MBLs) as a representative set, we demonstrate how QSFR properties are both conserved and varied across protein families. Similar to our characterizations on other protein families, the backbone flexibility of the five MBLs are overall visually conserved, yet there are interesting specific quantitative differences. For example, the plasmid-encoded NDM-1 enzyme, which leads to a fast spreading drug-resistant version of Klebsiella pneumoniae, has several regions of significantly increased rigidity relative to the other four. In addition, the set of intramolecular couplings within NDM-1 are also atypical. While long-range couplings frequently vary significantly across protein families, NDM-1 is distinct because it has limited correlated flexibility, which is isolated within the active site S3/S4 and S11/H6 loops. These loops are flexibly correlated in the other members, suggesting it is important to function, but the others also have significant amounts of correlated flexibility throughout the rest of their structures.

SUBMITTER: Brown MC

PROVIDER: S-EPMC4676803 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A case study comparing quantitative stability-flexibility relationships across five metallo-β-lactamases highlighting differences within NDM-1.

Brown Matthew C MC Verma Deeptak D Russell Christian C Jacobs Donald J DJ Livesay Dennis R DR

Methods in molecular biology (Clifton, N.J.) 20140101

The Distance Constraint Model (DCM) is an ensemble-based biophysical model that integrates thermodynamic and mechanical viewpoints of protein structure. The DCM outputs a large number of structural characterizations that collectively allow for Quantified Stability-Flexibility Relationships (QSFR) to be identified and compared across protein families. Using five metallo-β-lactamases (MBLs) as a representative set, we demonstrate how QSFR properties are both conserved and varied across protein fam ...[more]

PMID: 24061924

Similar Datasets

Project description:Numerous quantitative stability/flexibility relationships, within Escherichia coli thioredoxin (Trx) and its fragments are determined using a minimal distance constraint model (DCM). A one-dimensional free energy landscape as a function of global flexibility reveals Trx to fold in a low-barrier two-state process, with a voluminous transition state. Near the folding transition temperature, the native free energy basin is markedly skewed to allow partial unfolded forms. Under native conditions the skewed shape is lost, and the protein forms a compact structure with some flexibility. Predictions on ten Trx fragments are generally consistent with experimental observations that they are disordered, and that complementary fragments reconstitute. A hierarchical unfolding pathway is uncovered using an exhaustive computational procedure of breaking interfacial cross-linking hydrogen bonds that span over a series of fragment dissociations. The unfolding pathway leads to a stable core structure (residues 22-90), predicted to act as a kinetic trap. Direct connection between degree of rigidity within molecular structure and non-additivity of free energy is demonstrated using a thermodynamic cycle involving fragments and their hierarchical unfolding pathway. Additionally, the model provides insight about molecular cooperativity within Trx in its native state, and about intermediate states populating the folding/unfolding pathways. Native state cooperativity correlation plots highlight several flexibly correlated regions, giving insight into the catalytic mechanism that facilitates access to the active site disulfide bond. Residual native cooperativity correlations are present in the core substructure, suggesting that Trx can function when it is partly unfolded. This natively disordered kinetic trap, interpreted as a molten globule, has a wide temperature range of metastability, and it is identified as the "slow intermediate state" observed in kinetic experiments. These computational results are found to be in overall agreement with a large array of experimental data.

Dataset Information

A case study comparing quantitative stability-flexibility relationships across five metallo-?-lactamases highlighting differences within NDM-1.

Publications

A case study comparing quantitative stability-flexibility relationships across five metallo-β-lactamases highlighting differences within NDM-1.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure