1. Hydration Free Energy Profiles of Amino Acid Side Chains at Water-Air Interface Lomonosov Moscow State University Faculty of Biology Department of Bioengineering Alexey Shaytan alex@molsim.org

2. MSU founded 1755 39 faculties and 15 research institutions ~35 000 students ~5 000 PHD students ~10 000 research and faculty staff

3. Molecular Simulations Group Head – Prof. Konstantin V. Shaitan Associate Prof. – Nikolai K. Balabaev Research Staff Mikhail AntonovAlexey ShaytanValeriy Novoselezkii PHD students Students Marina Kasimova, Olesya Volokh, Mikhail Vishnepolskii Ann Popinako Tatiyana Naumenkova Marine Bozdaganyan Philipp Orekhov

4. Outline ) Free energies in MD simulations ) hydration free energies of amino acids ) validity of forcefields ) hydration of molecules at water/air interface ) free energy profiles ) adsorption free energies

5. Free energies and MD simulations Free energy refers to the amount of work that can be extracted from a system. F=E-TS F=-kT lnZ Thermodynamics Statistical physics H(p1,…,pN,x1,…,xN) Probability~const*exp(-H/kT)

6. Free energy governs the probability Protein-ligand binding

7. Biological system are in water F=E-TS Hydrophopic hydration: 1)energetically favorable 2)Entropically unfavorable

8. Common protein force fields CHARMM AMBER OPLS GROMOS TIP3P SPC SPC/E TIP4P TIP5P Parameterization: an initio + bulk properties + energetical properties

9. Hydration free energy F hydr – hydration free energy Water Air F hydr =-kTln(c1/c2) F hydr – free energy of coupling one solute molecule into the rest of solution “computational alchemistry methods”

10. Free energy calculations FEP TI BAR JE

11. Amino acid R-H-analogs Conformational simplicity is important

12. Hydration free energies (R-H-analogs) FF: OPLS-AA + SPC. R=0.997 Overest. 0- 4 kJ/mol

13. Hydration at interface Solvent accessible surface of a protein F ads – adsorption free energy Water Air F ads =-kTln(ca/c2) Hydrophobicity scale

14. Water-air interface Solute concentration C(z) C1C1 C2C2 W(z)=-kTln(C(z)) – free energy profile (PMF) F hydr =-kTln(C 2 /C 1 ) – hydration free energy

15. Constraint force algorithm

16. Water-interface system

17. surface potential drop is −0.59 V

18. Profiles

19. Hydration free energies

20. Adsorption energies -Gibbs excess

21. Adsorption energies

23. Experimental comparison Bull & Breese (1974) - adsorption energy scale for amino acids side chains Correlation is R=0.65 Experiment, kJ/molSimulation, kJ/mol Methanol-15.2-19.2 Experiment, 10^-10 mol/cm^-2Simulation, 10^-10 mol/cm^-2 Methanol2.51.2 Ethanol3-52.6 F hydr ~F bb +F R F ads ≠F bb +F R

24. Summary A.K. Shaytan, V.A. Ivanov, K.V. Shaitan, A.R. Khokhlov "Free energy profiles of amino acid side chain analogs near water-vapor interface obtained via MD simulations", // Journal of Computational Chemistry, 2010, 31(1), pp 204-216, DOI:10.1002/jcc.21267 ) We developed a rigorous methodology of estimating adsorption free energies at liquid/gas interface ) We statistically described the hydration process of small molecules as water/vapor interface ) Adsorption energies can be used for quality assessment and tuning of molecular forcefields

25. Thank you for attention!