Quantifying the energetics of highly conserved water molecules in carbohydrate- binding proteins. Elisa Fadda Computational Glycoscience Lab, School of.

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Quantifying the energetics of highly conserved water molecules in carbohydrate- binding proteins. Elisa Fadda Computational Glycoscience Lab, School of Chemistry, NUI Galway Design of Drugs and Chemicals that Influence Biology, IPAM, UCLA, Apr 4 th - 8 th 2011

Woods Glycoscience NUI Galway Summer 2010

Enzyme Re-engineering Inhibitors (Glycomimetics) Design “In house” Approach to NUIG Computational Predictions Biological Assays Virtual Glycan Array Screening CFG Screening

Computational NUIG o Carbohydrate-binding protein engineering o Protein-carbohydrate interaction and dynamics o Glycomimetics Fadda E. and Woods R.J., Drug. Disc. Today (2010), 15,

Common Classes of Animal Glycans

Carbohydrates facilitate the interaction between cells and: Other cells Viruses Bacteria Toxins

Influenza Viruses H5N1 Avian Flu (South East Asia), 2008A/H1N1 Swine Flu (Mexico), 2009

Influenza Virus H1N1 (Credits: Rob Ruigrok/ UVHCI) 009/html/detail_8.html

Flu Virus Infection ad Replication cation_discussion/molecule_of_the_mont h/pdb76_1.html 1) Hemagglutinin 2) Neuraminidase tion_discussion/molecule_of_the_month/pd b113_1.html 1.Virus binds sialic acid containing carbohydrates on the cell surface via hemagglutinins. 2.Virus delivers its genome into the host cell. 3.Produces new copies of the viral proteins. 4.Exits the cell while neuraminidases cleave the sialic acid from the glycans on the cell surface.

Glycomimetic Drug Design PDBID 3CL0 Fadda E. and Woods R.J., Drug. Disc. Today (2010), 15,

Polysaccharides Structure branched extremely flexible amphipathic

Legume Lectins: Concanavalin A Legume lectins use water molecules not only to bind the metals, but also for carbohydrate binding.

Carbohydrate binding a) Hbonds (enthalpic) b) Desolvation (entropic) Protein∙nH 2 O + Carb ∙mH 2 O → Complex ∙qH 2 O + (n+m-q)H 2 O “High” energy water Klein et al., Ang. Chem. (2008), 120, Lemieux, Acc. Chem. Res. (1996), 29, 373

Displacement of Structural Water Design of glycomimetics that displace structural water upon binding. Higher binding affinity due to gain in entropy for the release of well ordered water into bulk. Binding affinity of structural water.

HIV Protease Inhibitor Design Lam et al, Science (1994), 263, ; PDBid 1HVR

Structural water in Concanavalin A PDBid: 1CVN Kadirvelraj R. et al, J. Am. Chem. Soc. (2008), 130, Man-  -(1-6)-[Man-  -(1-3)]-Man R228 D16 N14

Structural water in Concanavalin A PDBid: 1CVN Man-  -(1-6)-[Man-  -(1-3)]-Man R228 D16 N14 PDBid: 3D4K

Questions o What is the energetic contribution that makes this water so highly conserved? o Water model dependence? o Is it possible to displace the water? o Why the synthetic ligand is not successful in displacing the structural water?

Standard Binding Free Energy “.. Then there is the dynamics vs. static problem: drug molecules and their binding targets never stop moving, folding and flexing. Modelling this realistically is hard, and increases the computational burden substantially.” D.Lowe, Nature, 7 May 2010

Double Decoupling Approach: Thermodynamic breakdown Pw (sol) P (sol) + w (gas) w (sol) w (gas) P (sol) + w (sol) Pw (sol) Gilson et al., Biophys J. (1997), 72, Hamelberg and McCammon, J. Am. Chem. Soc. (2004), 126,

Double Decoupling Approach Gilson et al., Biophys J. (1997), 72, Hamelberg and McCammon, J. Am. Chem. Soc. (2004), 126,

3- and 5-Site Water Models TIP3P § TIP5P* ModelqHqH  0 (kcal/mol)  Å) TIP3P TIP5P § Jorgensen et al., J. Chem. Phys. (1983), 79, 926 *Mahoney and Jorgensen, J. Chem. Phys. (2000), 112, 8910

 G w of 3- and 5-Site Water Models 25 Å ModelCoulombvdW G0G0 Lit. TIP3P8.5 (0.1)-2.2 (0.1) (0.4); 6.1 (0.2) TIP5P7.7 (0.1)-2.0 (0.1)5.7 - Desolvation free energies (all values in kcal/mol).

Free ConA (1GVK) 1GKBCoulombvdW TIP3P (0.1) TIP5P (0.2) Res-idbondDistance (Å) N14N-O W 2.9 D16O-O W 2.6 R228N-O W 3.0 N14 C  -O w 3.5 All values in kcal/mol Correction term of -3.0 kcal/mol

ConA/3MAN (1CVN) 1CVNCoulombvdW TIP3P (0.2) TIP5P (0.1) All values in kcal/mol Res-idbondDistance (Å) N14N-O W 2.7 D16O-O W 2.8 R228N-O W 3.1 MANO2-O w 2.4

ConA/3HET (3D4K) 3D4KCoulombvdW TIP3P TIP5P (0.1) -5.7 (0.2) All values in kcal/mol Res-idbondDistance (Å) N14N-O W 2.7 D16O-O W 2.5 R228N-O W 3.0 MANO8-O w 3.0

ConA/3HETConA/3MAN Standard Binding Free Energies (TIP3P) Free3MAN3HET Gb0Gb (0.1)-1.0 (0.2)-4.8 (0.1) All values in kcal/mol

ConA/3HETConA/3MAN Standard Binding Free Energies (TIP5P) Free3MAN3HET Gb0Gb (0.2)-7.1 (0.1)-5.7 (0.2) All values in kcal/mol

Changing vdW parameters:TIP3P-MOD TIP3P-MOD § § Sun and Kollman, J. Comp. Chem. (1995), 16(9), T3PT3P-MODT5P   kcal/mol)  (Å) q (O) q (H) Gh0Gh “By increasing the depth of the vdW well from kcal/mol to kcal/mol, the solvation energies of small alkanes improved compared to experimental data.”

ConA/3HETConA/3MAN Standard Binding Free Energies (TIP3P-MOD) Gb0Gb0 Free3MAN3HET TIP3P-MOD-0.3 (0.2)0.0 (0.2)-1.7 (0.2) TIP3P+0.1 (0.1)-1.0 (0.2)-4.8 (0.1) All values in kcal/mol

4-site water model TIP4P TIP3PTIP4P § TIP5P   kcal/mol)  (Å) q (O/M) q (H) Gh0Gh § Jorgensen et al., J. Chem. Phys. (1983), 79, 926

ConA/3HETConA/3MAN Standard Binding Free Energies (TIP4P) Gb0Gb0 Free3MAN3HET TIP4P-2.3 (0.1)-2.3 (0.3)0.2 (0.4) All values in kcal/mol

Does the water have a structural function in ConA? ModelFree3MAN3HET TIP3Punboundw. boundstructural TIP5Pstructural TIP3P-MODunbound w. bound TIP4Pstructural unbound it depends on the water model…

a) b) c) a) 3MAN Glycomimetic Candidates

Conclusions The choice of water model has a significant impact on the assessment and interpretation of standard binding free energies. Within the context of non-polarizable force fields, TIP5P 5-site model seems to be a step in the right direction. The water is not displaced by the synthetic ligand because it is able to preserve its tetrahedral coordination. A bulkier synthetic ligand (e.g. hydroxypropyl) might be able to form favourable vdW contacts with N14 C , with the OH replacing the water in the binding site.

Acknowledgements Prof. Rob Woods Oliver Grant Joanne Martin Hannah Smith Niall Walshe Dr. Nina Weisser Dr. Lori Yang Dr. Jen Hendel Dr. Marleen Renders Valerie Sickkids: Dr. Régis Pomès Chris Neale

Unbound ConA with TIP3P-MOD 1GKBCoulombvdW T3P+13.4 (0.3)-3.9 (0.2) (0.2) T5P+13.0 (0.5)-3.2 (0.3) (0.4) T3P-MOD+12.6 (0.2)-4.1 (0.2) (0.2) All values in kcal/mol WATER T3P+6.2 T5P+5.7 T3P-MOD+6.2* * Shirts and Pande, J. Chem. Phys. (2005), 122,

3D4K1CVN 1CVN vs. 3D4K (TIP5P) PDBidCoulombvdW ConA/3MAN18.3 (0.4)-5.5 (0.4) ConA/3HET16.8 (0.2)-4.2 (0.5) All values in kcal/mol Gb0Gb (0.4) -3.9 (0.4)