Computational full electron structure study of biological activity in Cyclophilin A

Abstract

Cyclosporine (CsA) is widely used in organ transplant patients to help prevent the patient’s body from rejecting the organ. CsA has been shown to be a safe and highly effective immunosuppressive drug that binds with the protein Cyclophilin A (CypA) at active sites. However, the exact mechanism of this binding at the molecular level remains unknown. In this project, we elucidate the binding of CsA to CypA at the molecular level by computing their electron structures and revealing their interactions. We employ a novel technique called electron Computer-Aided Drug Design (eCADD) on the protein’s full electron structure along with its hydrophobic pocket and the perturbation theory of the interaction between two wave functions. We have identified the wave function of CypA, the biological active residues and active atoms of CypA and CsA, the interaction site between CypA and CsA, and the hydrogen bonds in the ligand CsA binding site. All these calculated active residues, active atoms, and hydrogen bonds are in good agreement with recorded laboratory experiments and provide guidelines for designing new ligands of CypA. We believe that our eCADD framework can provide researchers with a cost-efficient new method of drug design based on the full electron structure of proteins.

Keywords:

• full electron structure calculation
• frontier orbital
• active residues
• active atoms
• protein–ligand interaction

Acknowledgements

The authors thank Professors Yuanjie Ye, Xun Wang and Ling Ye for their kind help, Dr Kaillathe Padmanadhan, Department of Biochemistry, Michigan State University, for providing the SGI machine, and the Department of Computer Science at Oakland University for providing the Linux cluster.

Notes

No potential conflict of interest was reported by the authors.