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

Lomonosov Moscow State UniversityFaculty of Biology

Department of Bioengineering

Alexey Shaytan

alex@molsim.org

MSU

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

Molecular Simulations Group

Head – Prof. Konstantin V. Shaitan

Associate Prof. – Nikolai K. Balabaev

Research Staff

Mikhail Antonov Alexey Shaytan Valeriy Novoselezkii

PHD students

Students Marina Kasimova, Olesya Volokh, Mikhail Vishnepolskii

Ann Popinako

TatiyanaNaumenkova

MarineBozdaganyan

PhilippOrekhov

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

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

The

rmod

ynam

ics

Sta

tistic

al p

hysi

cs H(p1,…,pN,x1,…,xN)

Probability~const*exp(-H/kT)

Free energy governs the probability

Protein-ligand binding

Biological system are in water

F=E-TS

Hydrophopic hydration:1)energetically favorable2)Entropically unfavorable

Common protein force fields

, , , , , ,

( ) ( ) ( ) ( ) [ ( ) ( )]b b b c vdwij ij ijk ijk ijkl ijkl ij ij ij ij

i j i j k i j k l i j

U r U b U U U r U r

•CHARMM•AMBER•OPLS•GROMOS

•TIP3P•SPC•SPC/E•TIP4P•TIP5P

Parameterization: an initio + bulk properties + energetical properties

Hydration free energy

Fhydr – hydration free energyWater

Air

Fhydr =-kTln(c1/c2)

Fhydr – free energy of coupling one solute molecule into the rest of solution

“computational alchemistry methods”

Free energy calculations

FEP

TI

BAR

JE

Amino acid R-H-analogs

Conformational simplicity is important

Hydration free energies (R-H-analogs)

FF: OPLS-AA + SPC.

R=0.997Overest. 0-4 kJ/mol

Hydration at interface

Solvent accessible surface of a protein

Fads – adsorption free energy

Water

Air

Fads =-kTln(ca/c2)

Hyd

roph

obic

ity s

cale

Water-air interfaceS

olut

e co

ncen

trat

ion

C(z)C1C2

W(z)=-kTln(C(z)) – free energy profile (PMF)

Fhydr=-kTln(C2/C1) – hydration free energy

Constraint force algorithm

Water-interface system

Water-interface system

surface potential drop is −0.59 V

Profiles

Hydration free energies

Adsorption energies

-Gibbs excess

Adsorption energies

Adsorption energies

Experimental comparison

Bull & Breese (1974) - adsorption energy scale for amino acids side chainsCorrelation is R=0.65

Experiment, kJ/mol Simulation, kJ/mol

Methanol -15.2 -19.2

Experiment, 10^-10 mol/cm^-2 Simulation, 10^-10 mol/cm^-2

Methanol 2.5 1.2

Ethanol 3-5 2.6

Fhydr~Fbb+FR

Fads≠Fbb+FR

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

Thank you for attention!