Hydration Free Energy Profiles of Amino Acid Side Chains at Water-Air Interface

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 Antonov Alexey Shaytan Valeriy Novoselezkii PHD students Philipp Orekhov Marine Bozdaganyan Ann Popinako Tatiyana Naumenkova Students Marina Kasimova, Olesya Volokh, Mikhail Vishnepolskii

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

6. Free energy governs the probability Protein-ligand binding

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

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

9. Hydration free energy Fhydr =-kTln(c1/c2) Water Fhydr – hydration free energy Air Fhydr – 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 Water Air Hydrophobicity scale Fads =-kTln(ca/c2) Solvent accessible surface of a protein Fads – adsorption free energy

14. Water-air interface C1 C2 C(z) W(z)=-kTln(C(z)) – free energy profile (PMF) Fhydr=-kTln(C2/C1) – hydration free energy Solute concentration

15. Constraint force algorithm

16. Water-interface system

17. Water-interface system surface potential drop is −0.59 V

18. Profiles

19. Hydration free energies

20. Adsorption energies -Gibbs excess

21. Adsorption energies

22. Adsorption energies

23. Experimental comparison Bull & Breese (1974) - adsorption energy scale for amino acids side chains Correlation is R=0.65 Fhydr~Fbb+FR Fads≠Fbb+FR

24. Summary • ) 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 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

25. Thank you for attention!