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New insights into prediction of weak ?-? complex association through proton-nuclear magnetic resonance analysis.

ABSTRACT: For analysis of weak ?-? complexes proton-nuclear magnetic resonance (proton-NMR) simultaneously provides information of stacking configurations and association constants [Formula: see text] However, an apparent issue for this approach is inconsistent/impossible constant estimation which often leads to unreasonable interpretation for ?-? complexation. Whether or not this proton-dependent constant variation could be attributed to simple experimental uncertainties or to more sophisticated additional unspecific shielding effects (AUS effects) was addressed by means of hypothesis tests using a robust bootstrap technique in this report. Our analysis shows the significance of AUS effects on such variation in constant estimation. A following study using numeric simulation further reveals the variation patterns induced by AUS effects and concludes that the largest [Formula: see text] among the obtained [Formula: see text] estimates of a complex is considered as the best estimate of [Formula: see text] due to minimum deviation from the true value of K and the multiple [Formula: see text] estimates of a ?-? complex could provide preferable inferences for complex geometries.

SUBMITTER: Lin C

PROVIDER: S-EPMC7602360 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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New insights into prediction of weak π-π complex association through proton-nuclear magnetic resonance analysis.

Lin Chenyu C Skufca Joseph J Partch Richard E RE

BMC chemistry 20201030 1

For analysis of weak π-π complexes proton-nuclear magnetic resonance (proton-NMR) simultaneously provides information of stacking configurations and association constants [Formula: see text] However, an apparent issue for this approach is inconsistent/impossible constant estimation which often leads to unreasonable interpretation for π-π complexation. Whether or not this proton-dependent constant variation could be attributed to simple experimental uncertainties or to more sophisticated addition ...[more]

PMID: 33292404

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Project description:Protein kinases are ubiquitous enzymes with critical roles in cellular processes and pathology. As a result, researchers have studied their activity and regulatory mechanisms extensively. Thousands of X-ray structures give snapshots of the architectures of protein kinases in various states of activation and ligand binding. However, the extent of and manner by which protein motions and conformational dynamics underlie the function and regulation of these important enzymes is not well understood. Nuclear magnetic resonance (NMR) methods provide complementary information about protein conformation and dynamics in solution. However, until recently, the large size of these enzymes prevented researchers from using these methods with kinases. Developments in transverse relaxation-optimized spectroscopy (TROSY)-based techniques and more efficient isotope labeling strategies are now allowing researchers to carry out NMR studies on full-length protein kinases. In this Account, we describe recent insights into the role of dynamics in protein kinase regulation and catalysis that have been gained from NMR measurements of chemical shift changes and line broadening, residual dipolar couplings, and relaxation. These findings show strong associations between protein motion and events that control kinase activity. Dynamic and conformational changes occurring at ligand binding sites and other regulatory domains of these proteins propagate to conserved kinase core regions that mediate catalytic function. NMR measurements of slow time scale (microsecond to millisecond) motions also reveal that kinases carry out global exchange processes that synchronize multiple residues and allosteric interconversion between conformational states. Activating covalent modifications or ligand binding to form the Michaelis complex can induce these global processes. Inhibitors can also exploit the exchange properties of kinases by using conformational selection to form dynamically quenched states. These investigations have revealed that kinases are highly dynamic enzymes, whose regulation by interdomain interactions, ligand binding, and covalent modifications involve changes in motion and conformational equilibrium in a manner that can be correlated with function. Thus, NMR provides a unique window into the role of protein dynamics in kinase regulation and catalysis with important implications for drug design.

Dataset Information

New insights into prediction of weak ?-? complex association through proton-nuclear magnetic resonance analysis.

Publications

New insights into prediction of weak π-π complex association through proton-nuclear magnetic resonance analysis.

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