Exploring the Impact of Protein Chain Selection in Binding Energy Calculations with DFT.
Chemphyschem
; : e202400119, 2024 Aug 27.
Article
en En
| MEDLINE
| ID: mdl-39188152
ABSTRACT
Calculation of binding free energies between a protein and a ligand are highly desired for computer-aided drug design. Here we approximate the binding energies of ABL1, an enzyme which is the target for drugs used in the treatment of chronic myeloid leukaemia, with minimal models and density functional theory (DFT). Starting from the crystal structures of protein-drug complexes, we estimated the binding free energies having used all available individual molecules (protein chains) within each structure, not only a single one as commonly used, in order to see if the choice of the protein chain is important in such calculations. Diï¬erences were observed between chains in the same ï¬le. Energy decomposition analysis (EDA) revealed that the most important factors for binding were exchange, repulsion and electrostatics. The desolvation term varied dramatically between the inhibitors (between 4.2 and 92.3 kcal/mol). All functionals showed similar patterns in the EDA and in discriminating between the ligands. Non-covalent interactions (NCI) analysis was used to further explain the diï¬erences between protein chains and functionals. Overall, it is shown that small minimal models of a drug binding site can be useful to infer on the suitability of an initial crystal structure for further analysis such as EDA.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Chemphyschem
Asunto de la revista:
BIOFISICA
/
QUIMICA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Suecia
Pais de publicación:
Alemania