How does conformational flexibility influence key structural features involved in activation of anaplastic lymphoma kinase?

Anaplastic Lymphoma Kinase (ALK) plays a major role in developing tumor processes and therefore has emerged as a validated therapeutic target. Applying atomistic molecular dynamics simulations on the wild type enzyme and the nine most frequently occurring and clinically important activation mutants we revealed important conformational effects on key interactions responsible for the activation of the enzyme.

Structural and computational enzymology: bringing experiments and computations together.

In this introductory chapter, we present how the experimental and computational strategies in enzyme research are developed and how they complement each other to provide better insights for understanding enzyme structures and mechanisms.

Integrated synthetic, pharmacological, and computational investigation of cis-2-(3,5-dichlorophenylcarbamoyl)cyclohexanecarboxylic acid enantiomers as positive allosteric modulators of metabotropic glutamate receptor subtype 4.

2-(3,5-Dichlorophenylcarbamoyl)cyclohexanecarboxylic acid (1) is a potent and selective positive allosteric modulator of metabotropic glutamate receptor subtype 4 (mGluR4). The activity of 1 was reported to reside in the cis diastereomer with equal potency between its enantiomeric forms (Niswender et al., Mol.

Mechanisms of protein circular dichroism: insights from computational modeling.

Chirality is a fundamental property of molecular systems, and stereoselectivity underlines many fundamental biomolecular processes like biological recognition and catalysis. Circular dichroism (CD) which is a consequence of molecular chirality is an important method for the investigation of protein structure and structural changes during interactions with ligands, mutations, and folding. The development of computational methods allows powerful insight to be provided into the mechanisms of generation of CD spectra in complex systems as proteins and to explain experimental data, to validate predicted structures, and to explain fine details of biomolecular interactions.

Individual contributions of the aromatic chromophores to the near-UV Circular Dichroism in class A beta-lactamases: A comparative computational analysis.

Class A beta-lactamases are enzymes which are responsible for the bacterial resistance against antibiotics and therefore are of great importance in rational inhibitor design. In this paper we comparatively analyze all the individual contributions of the aromatic chromophores in three class A beta-lactamases (from Staphylococcus aureus, Streptomyces albus and Bacillus licheniformis) to their near-UV Circular Dichroism. The analysis is performed using recently developed procedure based on established theoretical method.

Relationship between chiroptical properties, structural changes and interactions in enzymes: a computational study on beta-lactamases from class A.

Enzyme functions such as catalysis, binding and regulation are directly related to a variety of conformational changes. A sensitive and useful method for their investigation is circular dichroism (CD) and a rotational strength (R) is its fundamental characteristic. In this study, we show how the sensitivity of the mechanisms of rotational strengths to important conformational changes depends on the chromophore environment in two beta-lactamases from class A (from Escherichia coli and B.