Quantum Mechanical Evaluation of Charge Transfer inside Proteins

IONESCU, Crina-Maria, Radka SVOBODOVÁ VAŘEKOVÁ and Jaroslav KOČA. Quantum Mechanical Evaluation of Charge Transfer inside Proteins. In 3rd Strasbourg Summer School in Chemoinformatics. 2012.

Basic information

Original name

Quantum Mechanical Evaluation of Charge Transfer inside Proteins

Authors

IONESCU, Crina-Maria, Radka SVOBODOVÁ VAŘEKOVÁ and Jaroslav KOČA

Edition

3rd Strasbourg Summer School in Chemoinformatics, 2012

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Other information

Type of outcome

Prezentace na konferencích

Confidentiality degree

není předmětem státního či obchodního tajemství

Keywords in English

proteins, charge transfer, quantum mechanics

Tags

International impact

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Abstract

V originále

Proteins are central to all aspects of a cell's life, and consequently make up the bulk of all drug targets. Yet studying proteins and their interactions by computational methods is challenging due to the complex nature of proteins as long, non-neutral molecular chains with complex 3D assembly and conformational flexibility. Moreover, the inclusion of solvent effects is often critical for a proper evaluation of biological activity. Especially in the case where large libraries of drug-like ligands are tested for activity against a protein target, it is clear that the protein can only be treated in a very approximate way with respect to flexibility and electrostatics. However, aspects of atomic interaction such as charge transfer are completely overlooked in these simulations due to the complexity of such a calculation, despite the fact that charge transfer was found to be significant in many biomolecular interactions, and functionally linked to protein structural dynamics [1]. One aspect of the problem is related to partial atomic charges, which are commonly used for the calculation of the electrostatic component of biomolecular interactions, and for the estimation of ligand binding energies. It has already been shown that the use of accurate partial atomic charges can make the difference between irrelevant and accurate predictions related to the activity of a protein or the activity of a potential drug molecule towards a protein [2,3]. A much less investigated aspect is that most molecular simulation methods and software tools typically consider that all amino acid residues have integral total charge. Recent investigations provided clear evidence that for ubiquitin [4,5] and bovine pancreatic trypsin inhibitor [6] the net amino acid charge distribution inside the protein differs significantly from the conventions used by established computational models. These studies ultimately suggest that charge transfer inside proteins is indeed non-negligible, and that this aspect can be properly evaluated only under QM treatment. Here we report on a robust, QM-level investigation to evaluate precisely how much charge can typically be transfered inside proteins and by which residues, what factors affect the amount and direction of charge transferred, and whether the results obtained in previous QM studies on specific proteins can be validated on a large and various set of protein fragments.