drug design intro - katedra fyzikální chemie...
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Karel Berka, Ph.D.
Martin Lepšík, Ph.D.
Pavel Polishchuk, Ph.D.
Thierry Langer, Ph.D.
Jana Vrbková, Ph.D.
3rd Advanced in silico Drug Design
KFC/ADDMolecular mechanics intro
UP Olomouc, 23.1.-26.1. 2018
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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
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Scale of MatterN
um
ber
of
ato
ms
-N
6,022·1023
1010
109
108
107
106
105
104
103
102
101
1
Time - t
0 1 as 1 fs 1 ps 1 ns 1 μs 1 ms 1 s+static 10-18s 10-15s 10-12s 10-9s 10-6s 10-3s
electron bond chemical water macromol. protein our
movement vibration reaction diffusion diffusion folding senses
macro – 1 mol (18 ml water)
Wheat genomHuman genom100 nm nanoparticle
15 nm nanoparticleribosomeHIV proteaseinzulinlipidsbenzenatom
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Scale of MatterN
um
ber
of
ato
ms
-N
6,022·1023
1010
109
108
107
106
105
104
103
102
101
1
Time - t
0 1 as 1 fs 1 ps 1 ns 1 μs 1 ms 1 s+static 10-18s 10-15s 10-12s 10-9s 10-6s 10-3s
electron bond chemical water macromol. protein our
movement vibration reaction diffusion diffusion folding senses
QMMD
MM
CG MD
oko
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MOLECULAR INTERACTIONS
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24.01.2018 KFC/KFCH - V - Vazby 6
Covalent and Noncovalent Interactions
• Different origin
Covalent Interactions – overlap of orbitals
Noncovalent Interactions – electricproperties of molecules
• Different properties (ΔG=ΔH-TΔS)
ΔE (kcal/mol) R (Å) entropy
CI - ~ 100 1.2 - 1.6 not important
NI - ~ 1 – 5 2.0 - 5.0 key property
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7
Molecular Mechanics
total energy is function of atom positions
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• Atoms „balls on springs“
• Bonds
• Angles
• Dihedrals
• Elektrostatic interactions
• vdW interactions
𝐸𝑃𝑂𝑇 = 𝑓(𝑥)
𝐸𝑃𝑂𝑇 =1
2𝑘(𝑟 − 𝑟0)
2
r0
r0
EPOT
8
Molecular Mechanics
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9
Force-field
202
rrk
E rb
202
k
Ea
0cos12
nk
Et
ij
ji
r
cr
qqE
04
1
12*
6*
2
ij
ij
ij
ij
ij
ijvdwr
r
r
rE
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COVALENT INTERACTIONS
Bonds
Angles
Dihedral angles
Improper torsions
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11
Covalent bond
Sharing of noncomplete electron orbitals
– gives valence electron configuration with greater stability than in isolated atoms
Internal electrons are intact
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Covalent BondPo
ten
tial
ener
gy
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Bond as a springPo
ten
tial
ene
rgy
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Bond types
• various covalent bonds have variousr0, bond distancek, force constant
• similar bonds share similar behavior in allmolecules, insensitive to environment
• Parameters are transferable => force fields
– AMBER, CHARMM, MARTINI, MMFF94, OPLS…
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Angle bending
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Torsions/Dihedrals
Proper dihedrals Improper Torsions
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NONCOVALENT INTERACTIONS
ElectrostaticInductionDispersionHydrophobicSpecials – Hydrogen bonding, Halogen bonding
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18
Motto:
Not despite the weakness but because of weakness the noncovalent interactions play a key role in biodispciplines
Pavel Hobza
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24.01.2018 KFC/KFCH - V - Vazby 19
Noncovalent interactionsChemistry - liquids
Physics - existence of molecular crystals
Biology - 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
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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=EE + EI + ED + ER
(+) – repulsive
(-) - attractive
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Coulombic Interaction
• Coulomb law
• Atomic centered partial charges
– RESP (Restrained ElectroStatic Potential fit)
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Induction/Polarization
• Around ions -> induced charges
• Usually neglected in FF
– FF with polarization are slow
• Might be important for chemical reactions
– QM/MM
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London Dispersion
• Instantaneous correlation between electronsinduces polarization
• Allways attractive
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(Pauli) Repulsion
• Increases exponentially with occupiedelectron orbital overlap
• Usually combined with dispersion
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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!
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24.01.2018 KFC/KFCH - V - Vazby 26
Dispersion bound complexes
-ΔE (kcal/mol)
Dimers of rare gasses 1 – 2
Benzen dimer (T, PD) 2.5
Stacked DNA bases 10 – 15
Intercalator...WC DNA base pair 30 - 50
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24.01.2018 KFC/KFCH - V - Vazby 27
DNA with and without dispersioninteraction
Černý, J., Kabeláč, M.,Hobza, P. , J. Am. Chem. Soc., 2008, 130, 16055
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24.01.2018 KFC/KFCH - V - Vazby 28
Special types of noncovalent interactions
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24.01.2018 KFC/KFCH - V - Vazby 29
2 3 4 5 Period
100°C
0°C
-100°C
H2O
HF
NH3
CH4
H2Te
HI
SbH3
SnH4
BOILING POINTS
Hydrogen bond
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24.01.2018 KFC/KFCH - V - Vazby 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)
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24.01.2018 KFC/KFCH - V - Vazby 31
Improper blue-shifting H-bonding
:• P.Hobza et al.: JPC A 102,
2501 (1998)benzene…H-X (X=CH3, CCl3, C6H5)
• P.Hobza, Z.Havlas: Chem. Rev. 100, 4253 (2000)improper, blue-shifting hydrogen bond
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24.01.2018 KFC/KFCH - V - Vazby 32
H-bondsX-H...Y
H-bond improp. H-bond
Elongation X-H Shortening X-H
red shift ν blue shift ν
↑ intensity intensity
H2O...HOH H2O...HCX3
(X=F,Cl,Br,I)
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Hydrophobic interaction
• Interactions water-waters (~5 kcal/mol/atom) are stronger than between nonpolar organiccompounds and water (~1 kcal/mol/atom)
• Entropically advantageous
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Halogen bondC-X...Z-Y
(X=Cl, Br, I; Z=N, O)
Electrostatic potential for H3CBr and F3CBr
Blue – positive, red – negative potential
0.015
-0.015
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Potential Energy Surface
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Exploring PES
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TAKE HOME MESSAGE
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Take Home Message
• Molecular mechanics is an approximation of molecular interactions
• Error-cancelation in most terms
• Noncovalent interactionsare strong in weakness
• Chemistry is hiking on potential energy surface