Understanding protein-ligand binding at the molecular level: Using swap-based methods to visualise binding free energy components

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1 Understanding protein-ligand binding at the molecular level: Using swap-based methods to visualise binding free energy components Christopher Woods, School of Chemistry, University of Bristol Advanced Computing Research Centre

2 Part 1: Protein-Ligand Binding ΔGbind Protein Complex Ligand

3 Biochemistry occurs in the aqueous phase

4 Absolute Binding Free Energy Calculations Protein(aq) Ligand(aq) ΔGbind Water (aq) Complex(aq)

5 Double Decoupling / Double Annihilation Protein(aq) ΔGbound Complex(aq) ΔGbind Ligand(aq) ΔGfree Water (aq)

6 WaterSwap Absolute binding free energy method Recognises the competition between the ligand and water for the protein binding site Woods et al., J. Chem. Phys., 134, , 2011 Woods et al., Faraday Trans., 169, , 2014

7 WaterSwap Protein(aq) Ligand(aq) ΔGbind Water (aq) Complex(aq)

8 Waterswap uses a λ-coordinate to swap a ligand and a water cluster between a protein box and a water box Protein Box Water Box

9 Waterswap uses a λ-coordinate to swap a ligand and a water cluster between a protein box and a water box Protein Box 100% 0% λ=0.0 Water Box

10 Waterswap uses a λ-coordinate to swap a ligand and a water cluster between a protein box and a water box Protein Box 80% 20% λ=0.2 Water Box

11 Waterswap uses a λ-coordinate to swap a ligand and a water cluster between a protein box and a water box Protein Box 50% 50% λ=0.5 Water Box

12 Waterswap uses a λ-coordinate to swap a ligand and a water cluster between a protein box and a water box Protein Box 20% 80% λ=0.8 Water Box

13 Waterswap uses a λ-coordinate to swap a ligand and a water cluster between a protein box and a water box Protein Box 0% 100% λ=1.0 Water Box

14 Integrating the free energy along this λ-coordinate leads directly to the absolute binding free energy

15 Integrating the free energy along this λ-coordinate leads directly to the absolute binding free energy ΔGbind

16 Testing against experiment

17 Simulation / kcal mol R 2 = Experiment / kcal mol -1

18 Waterswap uses a λ-coordinate to swap a ligand and a water cluster between a protein box and a water box Protein Box Water Box

19 per- Absolute binding free energy can be decomposed to residue contributions Protein Box Water Box

20 Residues can be color-coded based on whether they stabilise binding the ligand, or binding water Phe227 Phe227 Blue = Stabilises the ligand Red = Stabilises water

21 Can also decompose to visualise contribution from active-site water molecules Glu192 Asp189 Blue = Stabilises the ligand Red = Stabilises water Glu192

22 Displacing water by replacing m-chlorobenzyl with benzamidine systematically strengthens binding Christopher J. Woods, Maturos Malaisree, Julien Michel, Ben Long, Simon McIntosh-Smith and Adrian J. Mulholland Binding Affinity / kcal mol Ligand m-chlorobenzyl benzamidine gure S1. Experimentally measured binding affinities for the 10 ligands studied in this rk (m-chlorobenzyl) Muley, L, and et for al., the J. ten Med. benzamidine Chem., 53, analogs , Binding 2010 affinities are taken m Muley et al., doi: /jm (reference 32 in our paper).

23 Part 2: Mutation and Drug Resistance Wildtype Drug Resistant Mutant Woods et al., Biochemistry, 51, , 2012 Woods et al., Biochemistry, 52, , 2013

24 ProteinSwap Absolute binding free energy method comparing different protein mutants Recognises the competition between a wildtype and mutant protein for which one will bind the ligand, and which will bind water

25 ProteinSwap Wildtype Box Mutant Box (R292K)

26 ProteinSwap Wildtype Box 100% λ=0.0 Mutant Box (R292K) 0%

27 ProteinSwap Wildtype Box 80% λ=0.2 Mutant Box (R292K) 20%

28 ProteinSwap Wildtype Box 50% λ=0.5 Mutant Box (R292K) 50%

29 ProteinSwap Wildtype Box 20% λ=0.8 Mutant Box (R292K) 80%

30 ProteinSwap Wildtype Box 0% λ=1.0 Mutant Box (R292K) 100%

31 Integrating the free energy along this λ-coordinate leads directly to the preference for the wildtype or mutant to bind the ligand or water cluster Free Energy / kcal mol WT R292K 8.3 ± 0.8 kcal mol λ *Peramivir bound to WT and R292K H1N neuraminidase

32 Residue-based free energy decomposition Wildtype Blue = Stabilises the ligand R292K Mutant Red = Stabilises water

33 Difference in decomposition highlights impact of mutation R292K Mutant Blue = Stronger binding in mutant Red = Weaker binding in mutant

34 Comparing WT to E119G: E119G is resistant to peramivir D151 E119G R118 Peramivir = 3.0 ± 1.4 kcal mol-1 Blue = Stronger binding in mutant Red = Weaker binding in mutant

35 Comparing WT to E119G: E119G is not resistant to oseltamivir D151 E119G R118 Peramivir = 3.0 ± 1.4 kcal mol-1 Blue = Stronger binding in mutant Oseltamivir = 0.6 ± 0.8 kcal mol-1 Red = Weaker binding in mutant

36 WaterSwap and (soon) ProteinSwap are free command line tools available at

37 WaterSwap built into Flare

38 Conclusions WaterSwap and ProteinSwap let you rationalise protein-ligand binding at the molecular level ProteinSwap enables the effect of protein mutation on drug binding to be calculated and visualised Free command-line tool Commercial graphical interface

39 Acknowledgements Maturos Malaisree for setting up, running and analysing the simulations EPSRC and Cresset for funding Advanced Computing Research Centre for providing early access to BlueCrystal Phase4

40 Integrating the free energy along this λ-coordinate leads directly to the preference for the wildtype or mutant to bind the ligand or water cluster Free Energy / kcal mol WT R292K 8.3 ± 0.8 kcal mol λ *Peramivir bound to WT and R292K H1N neuraminidase

41 Mutant Wildtype is the negative of Wildtype Mutant 16 Free Energy / kcal mol R292K WT -7.7 ± 1.2 kcal mol λ *Peramivir bound to WT and R292K H1N neuraminidase

42 Closing Triangles Free Energy is a State Function R152K Wildtype 8.3±0.8 kcal mol -1 R292K E119G *Peramivir bound to WT, R292K, R152K and E119 H1N neuraminidase

43 Peramivir binding to WT and R292K mutant H1N1 NA Wildtype Blue = Stronger binding in mutant R292K Mutant Red = Weaker binding in mutant

44 Oseltamivir binding to WT and R292K mutant H1N1 NA Wildtype Blue = Stronger binding in mutant R292K Mutant Red = Weaker binding in mutant

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