Free energy calculations on HIV-PR drug complexes Oliver Kuhn Free energies & Resistance Free energy calculations L76V Alchemy on HIV-PR drug complexes Simplified Model Oliver Kuhn Zentrum f¨ ur medizinische Biotechnologie (ZMB) Universit¨ at Duisburg-Essen 22.04.10 - Arevir Meeting
Free energy Free energies & Resistance calculations on HIV-PR drug complexes Oliver Kuhn Free energies & Resistance L76V Alchemy Simplified Model ∆ G = − kT ln ( K i ) ≈ − kT ln ( IC 50 )
Free energy Free energies & Resistance calculations on HIV-PR drug complexes Oliver Kuhn Free energies & Resistance L76V Alchemy Simplified Model ∆ G = − kT ln ( K i ) ≈ − kT ln ( IC 50 ) ∆∆ G = ∆ G WT − ∆ G MUT ≈ − kT ln ( RF ) with RF = IC WT 50 IC MUT 50
Free energy Thermodynamic Integration - Cycle calculations on HIV-PR drug complexes Oliver Kuhn Free energies & Resistance L76V Alchemy Simplified Model ∆∆ G bind , L 76 V = ∆ G L 76 , binding − ∆ G V 76 , binding = ∆ G L 76 V , bound − ∆ G L 76 V , free
Free energy 2 times 3 times 9 simulations in water calculations on HIV-PR drug complexes Oliver Kuhn Free energies & Resistance L76V Alchemy Simplified Model
Free energy Thermodynamic Integration - Cycle calculations on HIV-PR drug complexes Oliver Kuhn Free energies & Resistance L76V Alchemy Simplified Model
Free energy Thermodynamic Integration - Result calculations on HIV-PR drug complexes Oliver Kuhn Free energies & Resistance step free energy change ∆∆ G L76V Alchemy 1 -0.14 Simplified Model 2 1.26 3 0.41 total 1.53 ◮ consistent with z-score data from geno2pheno ◮ Computation time: ≈ 2 months on 90 CPUs = 5400 cpu-days
Free energy MMPBSA - an endpoint method calculations on HIV-PR drug complexes Oliver Kuhn Free energies & Resistance L76V Alchemy Simplified Model ◮ considers bound and unbound states only ◮ most recently: procedure to get converged (reproducible) values ◮ Computation time: ≈ 360 cpu-days
Free energy MMPBSA - preliminary result calculations on HIV-PR drug complexes Oliver Kuhn system ∆ G exp ∆ H T ∆ S ∆ G calc 3x - APV -11.7 -40 -22.9 -17.1 Free energies & Resistance WT - APV -12.6 -38 -23.3 -14.7 L76V Alchemy 3x - DRV -13.7 -41 -23.2 -17.8 Simplified Model WT - DRV -15.2 -44 na na 7 600 6 500 5 400 4 Frequency Frequency 300 3 200 2 100 1 0 0 −60 −50 −40 −30 −20 −40 −30 −20 −10 0 ∆ H T ∆ S 3x: L63P V82T I84V
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