1. Pentacycloundecane lactam vs lactone norstatine type HIV protease inhibitors: binding energy calculations and DFT study B.Honarparvar, H.G. Kruger, T. Govender, G.E. M. Maguire Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, South Africa Honarparvar@ukzn.ac.za December 2013

2. Structures of PCU-lactam-EAIS, its tautomer PCU-lactim- EAIS, PCU-lactone-EAIS inhibitors and PCU-models

3.  MD simulation  Binding free energy calculations  DFT study Objectives

4. Software: Amber12 Method: MMPB(GB)SA Binding free energy calculations

5. PCU- peptide inhibitor inside the active site of South African HIV protease

6. PCU-peptide inhibitor docked to HIV protease

7. The MM-PB(GB)SA method can be conceptually summarized as: ΔG bind = G complex – (G enzyme + G ligand ) where G complex, G enzyme and G ligand are the free energies of the complex, the enzyme and the ligand, respectively. MM-PB(GB)SA binding free energy calculations

8. Binding free energies and its components for the PCU-models complexed with the HIV protease PCU-modelsΔE ELE ΔE VDW ΔE SOL ( PB) ΔE SOL (G B) ΔG bind (PB SA) ΔG bind (GBS A) PCU-lactam(a)-1.48-34.1328.7311.34-29.52-27.63 PCU-lactam(b)-1.88-30.1422.4414.99-29.69-19.99 PCU-lactim(a)-12.23-30.1433.9221.01-29.85-24.78 PCU-lactim(b)-9.52-31.0733.6322.76-27.85-20.98 PCU-lactone(a)-2.51-25.6116.9513.34-28.19-17.37 PCU-lactone(b)-5.30-27.2618.4017.53-23.39-17.92

9. Binding free energies and its components for the PCU-peptides complexed with the HIV protease PCU-peptidesΔE ELE ΔE VDW ΔE SOL ( PB) ΔE SOL (G B) ΔG bind (PB SA) ΔG bind (G BSA) PCU-lactam-NH-EAIS(a) -29.39-68.4152.8153.46-69.79-61.74 PCU-lactam-NH-EAIS(b) -19.65-60.6749.9741.95-64.39-43.19 PCU-lactim-NH-EAIS(a) -30.39-71.4880.9055.23-68.07-54.33 PCU-lactim-NH-EAIS(b) -21.94-68.3662.3143.20-72.54-54.48 PCU-lactone-CO-EAIS(a) -24.22-55.0293.7387.38-61.77-37.99 PCU-lactone-CO-EAIS(b) -29.39-68.4152.8153.46-69.79-61.74

10. Binding free energies and its components for the synthesized PCU-peptides complexed with the HIV protease PCU-peptidesΔE ELE ΔE VDW ΔE SOL ( PB) ΔE SOL (G B) ΔG bind (P BSA) ΔG bind ( GBSA) PCU-lactam-CO-EAIS(a) -23.21-74. 82117.34106.88-87.89-58.79 PCU-lactam-CO-EAIS(b) -28.45-69.76123.8499.49-61.99-40.02 PCU-lactim-CO-EAIS(a) -11.87-59.9956.6937.49-55.37-55.99 PCU-lactim-CO-EAIS(b) -21.94-68.3662.3143.20-54.77-72.54 PCU-lactone-NH-EAIS(a) -19.50-74.3173.4946.27-67.41-55.34 PCU-lactone-NH-EAIS(b) -9.01-74.0852.5534.55-78.71-57.10

11. Software: Gaussian09 Method: B3LYP Basis set: 6-311G** DFT study of PCU-models

12. Electronic structure properties  NBO Analysis Polarizability Electrostatic Potential Map  (HOMO- LUMO) Natural atomic charges

13. Natural atomic charges (a.u.) on nitrogen and oxygen nuclei of PCU-models AtomLactam Lactim Lactone N 1 /O 1 -0.65213 -0.56236 -0.58068 O2O2 -0.63617 -0.69693 -0.59012 O3O3 -0.74727 -0.73899 -0.73981 N4N4 -0.65298 -0.65717 -0.60787 O5O5 -0.63987 -0.62519 -0.65063

14. Electrostatic Potential Map PCU-lactim PCU-lactam PCU-lactone

15. The frontiers orbitals of PCU-models (a) HOMO for Lactam (b) LUMO for Lactam (a) HOMO for Lactim (b) LUMO for Lactim (a) HOMO for Lactone (b) LUMO for Lactone

16. Polarizability (Å 3 ), dipole moment (Debye) and Gibbs free solvation energy ∆G solv (kcal/mol) values of the PCU-models PCU-modelsα (Å 3 )µ (Debye) ∆G Solv (kcal/mol) PCU-lactam81.2186.4726-17.925 PCU-lactim81.6633.5616-17.085 PCU-lactone79.3241.2617-8.893

17. Acknowledgements We thank the National Research Foundation for financial support, UKZN, and the CHPC (www.chpc.ac.za) for computational resources.www.chpc.ac.za

18. Thank you for your kind attention