Free energy calculations L76V Alchemy on HIV-PR drug complexes - - PowerPoint PPT Presentation

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Oct 03, 2023 39 likes •131 views

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)

SLIDE 1

Free energy calculations

n HIV-PR drug

complexes Oliver Kuhn Free energies & Resistance L76V Alchemy Simplified Model

Free energy calculations

n HIV-PR drug complexes

Oliver Kuhn

Zentrum f¨ ur medizinische Biotechnologie (ZMB) Universit¨ at Duisburg-Essen

22.04.10 - Arevir Meeting

SLIDE 2

Free energy calculations

n HIV-PR drug

complexes Oliver Kuhn Free energies & Resistance L76V Alchemy Simplified Model

Free energies & Resistance

∆G = −kT ln(Ki) ≈ −kT ln(IC50)

SLIDE 3

Free energy calculations

n HIV-PR drug

complexes Oliver Kuhn Free energies & Resistance L76V Alchemy Simplified Model

Free energies & Resistance

∆G = −kT ln(Ki) ≈ −kT ln(IC50) ∆∆G = ∆GWT−∆GMUT ≈ −kT ln(RF) with RF = IC WT

50

IC MUT

50

SLIDE 4

Free energy calculations

n HIV-PR drug

complexes Oliver Kuhn Free energies & Resistance L76V Alchemy Simplified Model

Thermodynamic Integration - Cycle

∆∆Gbind,L76V = ∆GL76,binding−∆GV 76,binding = ∆GL76V ,bound−∆GL76V ,free

SLIDE 5

Free energy calculations

n HIV-PR drug

complexes Oliver Kuhn Free energies & Resistance L76V Alchemy Simplified Model

2 times 3 times 9 simulations in water

SLIDE 6

Free energy calculations

n HIV-PR drug

complexes Oliver Kuhn Free energies & Resistance L76V Alchemy Simplified Model

Thermodynamic Integration - Cycle

SLIDE 7

Free energy calculations

n HIV-PR drug

complexes Oliver Kuhn Free energies & Resistance L76V Alchemy Simplified Model

Thermodynamic Integration - Result

step free energy change ∆∆G 1

0.14

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

SLIDE 8

Free energy calculations

n HIV-PR drug

complexes Oliver Kuhn Free energies & Resistance L76V Alchemy Simplified Model

MMPBSA - an endpoint method

◮ considers bound and unbound states only ◮ most recently:

procedure to get converged (reproducible) values

◮ Computation time: ≈ 360 cpu-days

SLIDE 9

Free energy calculations

n HIV-PR drug

complexes Oliver Kuhn Free energies & Resistance L76V Alchemy Simplified Model

MMPBSA - preliminary result

system ∆Gexp ∆H T∆S ∆Gcalc 3x - APV

11.7
40
22.9
17.1

WT - APV

12.6
38
23.3
14.7

3x - DRV

13.7
41
23.2
17.8

WT - DRV

15.2
44

na na

Frequency

−60 −50 −40 −30 −20 100 200 300 400 500 600

∆H

Frequency

−40 −30 −20 −10 1 2 3 4 5 6 7

Free energy calculations

Oliver Kuhn

Zentrum f¨ ur medizinische Biotechnologie (ZMB) Universit¨ at Duisburg-Essen

22.04.10 - Arevir Meeting

Free energies & Resistance

∆G = −kT ln(Ki) ≈ −kT ln(IC50)

Free energies & Resistance

∆G = −kT ln(Ki) ≈ −kT ln(IC50) ∆∆G = ∆GWT−∆GMUT ≈ −kT ln(RF) with RF = IC WT

50

IC MUT

50

Thermodynamic Integration - Cycle

∆∆Gbind,L76V = ∆GL76,binding−∆GV 76,binding = ∆GL76V ,bound−∆GL76V ,free

2 times 3 times 9 simulations in water

Thermodynamic Integration - Cycle

Thermodynamic Integration - Result

step free energy change ∆∆G 1

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

MMPBSA - an endpoint method

◮ considers bound and unbound states only ◮ most recently:

procedure to get converged (reproducible) values

◮ Computation time: ≈ 360 cpu-days

MMPBSA - preliminary result

system ∆Gexp ∆H T∆S ∆Gcalc 3x - APV

WT - APV

3x - DRV

WT - DRV

na na

∆H

T∆S

3x: L63P V82T I84V