3rd Advanced in silico Drug Design KFC/ADD Molecular mechanics intro Karel Berka, Ph.D. Martin Lepšík, Ph.D. Pavel Polishchuk, Ph.D.

Transcription

1 3rd Advanced in silico Drug Design KFC/ADD Molecular mechanics intro Karel Berka, Ph.D. Martin Lepšík, Ph.D. Pavel Polishchuk, Ph.D. Thierry Langer, Ph.D. Jana Vrbková, Ph.D. UP Olomouc,

2 Motto A theory is something nobody believes, except the person who made it An experiment is something everybody believes, except the person who made it Albert Einstein 2

3 Number of atoms - N Scale of Matter 6, macro 1 mol (18 ml water) Wheat genom Human genom 100 nm nanoparticle 15 nm nanoparticle ribosome HIV protease inzulin lipids benzen atom Time - t 0 1 as 1 fs 1 ps 1 ns 1 μs 1 ms 1 s+ static s s s 10-9 s 10-6 s 10-3 s electron bond chemical water macromol. protein our movement vibration reaction diffusion diffusion folding senses

4 Number of atoms - N Scale of Matter oko 6, MM QM CG MD MD Time - t 0 1 as 1 fs 1 ps 1 ns 1 μs 1 ms 1 s+ static s s s 10-9 s 10-6 s 10-3 s electron bond chemical water macromol. protein our movement vibration reaction diffusion diffusion folding senses

5 MOLECULAR INTERACTIONS

6 Covalent and Noncovalent Interactions Different origin Covalent Interactions overlap of orbitals Noncovalent Interactions electric properties of molecules Different properties (ΔG=ΔH-TΔS) ΔE (kcal/mol) R (Å) entropy CI - ~ not important NI - ~ key property KFC/KFCH - V - Vazby 6

7 Molecular Mechanics total energy is function of atom positions 7

8 Molecular Mechanics Atoms balls on springs Bonds r 0 E POT = f(x) E POT Angles Dihedrals r 0 E POT = 1 2 k(r r 0) 2 Elektrostatic interactions vdw interactions 8

9 Force-field E b kr 2 r r 2 0 E t k E 2 a 0 2 k 1 cos n E c r q i r q ij j 0 E vdw 2 ij r r * ij ij 6 ij r r * ij ij 12 9

10 Bonds Angles Dihedral angles Improper torsions COVALENT INTERACTIONS

11 Covalent bond Sharing of noncomplete electron orbitals gives valence electron configuration with greater stability than in isolated atoms Internal electrons are intact 11

12 Potential energy Covalent Bond

13 Potential energy Bond as a spring

14 Bond types various covalent bonds have various r 0, bond distance k, force constant similar bonds share similar behavior in all molecules, insensitive to environment Parameters are transferable => force fields AMBER, CHARMM, MARTINI, MMFF94, OPLS

15 Angle bending

16 Torsions/Dihedrals Proper dihedrals Improper Torsions

17 Electrostatic Induction Dispersion Hydrophobic Specials Hydrogen bonding, Halogen bonding NONCOVALENT INTERACTIONS

18 Motto: Not despite the weakness but because of weakness the noncovalent interactions play a key role in biodispciplines Pavel Hobza 18

19 Noncovalent interactions Chemistry Physics Biology - liquids - existence of molecular crystals - dominant - molecular recognition - macromolecular structure and function On the one hand, they should be strong enough to ensure the preferential binding but on the other hand they should be weak enough to allow disruption of bonding J. Watson on role of noncovalent interactions in DNA KFC/KFCH - V - Vazby 19

20 Types of noncovalent interactions Coulombic (Electrostatic) (+,-) ~r -1 - r -3 perm.multipole-perm.multipole Induction (polarization) (-) ~r -5 perm.multipole-ind.multipole London dispersion (-) ~r -6 inst.multipole-inst.multipole Repulsion (+) ~e -αr (r -12 ) (Pauli) electron exchange ΔE=E E + E I + E D + E R (+) repulsive (-) - attractive 20

21 Coulombic Interaction Coulomb law Atomic centered partial charges RESP (Restrained ElectroStatic Potential fit)

22 Induction/Polarization Around ions -> induced charges Usually neglected in FF FF with polarization are slow Might be important for chemical reactions QM/MM

23 London Dispersion Instantaneous correlation between electrons induces polarization Allways attractive

24 (Pauli) Repulsion Increases exponentially with occupied electron orbital overlap Usually combined with dispersion

25 Van der Waals term Lennard-Jones Potential Why is LJ potencial 12-6 computationally effective? Enumeration of square is quick r 12 = (r 6 ) 2. Repulsion increases exponentically!

26 Dispersion bound complexes -ΔE (kcal/mol) Dimers of rare gasses 1 2 Benzen dimer (T, PD) 2.5 Stacked DNA bases Intercalator...WC DNA base pair KFC/KFCH - V - Vazby 26

27 DNA with and without dispersion interaction Černý, J., Kabeláč, M.,Hobza, P., J. Am. Chem. Soc., 2008, 130, KFC/KFCH - V - Vazby 27

28 Special types of noncovalent interactions KFC/KFCH - V - Vazby 28

29 Hydrogen bond BOILING POINTS 100 C H 2 O 0 C -100 C HF NH 3 H 2 Te HI SbH 3 SnH 4 CH Period KFC/KFCH - V - Vazby 29

30 Elektrostatic Origin of H-bonding X-H...Y X-H elongates Elongation of X-H bond increases dipole of donor dipole-dipole electrostatic energy attraction red shift in IR spectrum (longer vibrations) KFC/KFCH - V - Vazby 30

31 Improper blue-shifting H-bonding : P.Hobza et al.: JPC A 102, 2501 (1998) benzene H-X (X=CH 3, CCl 3, C 6 H 5 ) P.Hobza, Z.Havlas: Chem. Rev. 100, 4253 (2000) improper, blue-shifting hydrogen bond KFC/KFCH - V - Vazby 31

32 H-bonds X-H...Y H-bond Elongation X-H red shift ν intensity H2O...HOH improp. H-bond Shortening X-H blue shift ν intensity H2O...HCX3 (X=F,Cl,Br,I) KFC/KFCH - V - Vazby 32

33 Hydrophobic interaction Interactions water-waters (~5 kcal/mol/atom) are stronger than between nonpolar organic compounds and water (~1 kcal/mol/atom) Entropically advantageous

34 Halogen bond C-X...Z-Y (X=Cl, Br, I; Z=N, O) Electrostatic potential for H3CBr and F3CBr Blue positive, red negative potential 34

35 Potential Energy Surface

36 Exploring PES

37 TAKE HOME MESSAGE

38 Take Home Message Molecular mechanics is an approximation of molecular interactions Error-cancelation in most terms Noncovalent interactions are strong in weakness Chemistry is hiking on potential energy surface