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Molecular determinants for ATP-binding in proteins: a data mining and quantum chemical analysis
Lisong Mao1, Yanli Wang, Yuemin Liu
1Department of Chemistry, University of Toledo, Toledo, OH 43606-3390, USA.
Journal of Molecular Biology
|April 21, 2004
Summary
Protein interactions with adenosine 5'-triphosphate (ATP) are vital. This study reveals that hydrogen bonding, pi-pi stacking, and cation-pi interactions are all crucial for adenine recognition in proteins, impacting drug design.
Area of Science:
- Biochemistry
- Structural Biology
- Computational Chemistry
Background:
- Adenosine 5'-triphosphate (ATP) is fundamental to all life.
- Understanding how proteins recognize ATP is critical for enzymatic mechanisms and drug development.
Purpose of the Study:
- To analyze the molecular determinants governing the recognition of the adenine moiety of ATP by proteins.
- To investigate the roles of hydrogen bonding, pi-pi stacking, and cation-pi interactions in adenine binding.
Main Methods:
- Large-scale data mining of the Protein Data Bank (PDB) for 68 non-redundant, high-resolution crystal structures.
- Systematic analysis of non-bonded intermolecular interactions between adenine and protein residues.
- High-level quantum chemical analysis (MP2/6-311 + G*) of interaction energies.
Main Results:
- Hydrogen bonding, pi-pi stacking, and cation-pi interactions are all significant for adenine recognition.
- On average, complexes exhibit 2.7 hydrogen bonds, 1.0 pi-pi stacking, and 0.8 cation-pi interactions.
- Quantum chemical analysis confirmed substantial interaction strengths for all three interaction types.
Conclusions:
- The study establishes the molecular basis for adenine recognition in proteins.
- Findings will aid in the rational design of enzyme inhibitors targeting ATP-binding sites, such as kinase inhibitors.