molecular_modeling

7/27/2019 Molecular_Modeling

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BasicsMolecular Modeling, lecture 1


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The course

Biomolecular structure Formation

Interaction

Sequence structure function

Mechanics of biomolecules

Modelling & simulation methods Analyzing computer simulation results


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Book

Andrew R. LeachMolecular Modelling - Principles andApplications, 2nd editionPrentice Hall 2001, ISBN 0582382106


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Practicalities

Lecturers:Berk Hess ([email protected])Bjrn Wallner ([email protected])

Lab exercises:Samuel Murail ([email protected])Torben Brmstrup ([email protected])

Lab reports: due one week after eachexercise
mailto:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]


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Schedule

Tentitative schedule is up at:

http://www.dbb.su.se/Teaching/Courses/Molecular_Modeling

exam: Friday December 17, 9:00-14:00
http://www.dbb.su.se/Teaching/Courses/Molecular_Modelinghttp://www.dbb.su.se/Teaching/Courses/Molecular_Modelinghttp://www.dbb.su.se/Teaching/Courses/Molecular_Modelinghttp://www.dbb.su.se/Teaching/Courses/Molecular_Modelinghttp://www.dbb.su.se/Teaching/Courses/Molecular_Modeling


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Why computer simulations?

Two primary roles:

Numerical experimentsneeds accuracy

Model testing

needs reductionism

Computers are fast enoughfor numerical experiments

Most models are toocomplicated for purelytheoretical reasoning

Allen&Tildesley


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Molecular modeling

Molecular modeling in biomolecules:mostly numerical experiments

Aim: prediction of macroscopicproperties

Ensemble averages/static properties(binding constants, etc.)

Dynamic properties (rates, mechanisms) Molecular scale: quantum-mechanical


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Time scales

10-15s 10-12s 10-9s 10-6s 10-3s 100s 103s

Biological Experiments

Molecular dynamics

QM simulations(Atomic detail)

(Electrons)

Coarse-grained models

(Whole proteins)


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Quantum mechanical simulations

Necessary to describe: electrons & bond formation

hydrogen (sometimes)

Currently at most ~100 atoms

Usually no time dependence

Heavy atoms can be treated classicallyanyway: need to coarse-grain!


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Atomic-scale simulations

Coarse grained: needs force fields fromquantum mechanical simulations

Good description level for understandingindividual proteins & simple interactions

Can simulate protein dynamics up to

~10s


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Protein structure

d


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Protein dynamics


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Water

Most ubiquitousmolecule in life: water

Forms hydrogen bonds

Strong interaction:~20 kJ/mol, or 8.4 kBT

Completelydetermines protein

structure: responsiblefor hydrophobicity.

d h b


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Hydrophobicity

Cavities in water disfavored:

small cavities disrupthydrogen bond network

big cavities form surfaces:hydrophobic effect

N l i id


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Natural amino acids

P id


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Peptide structure

Backbone degrees of freedom:

Peptide () bond (trans/cis for Pro)

(C-N-CA-C)

(N-CA-C-N) torsions

Side chain degrees of freedom:

1,2,3 torsions

P id


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Peptide structure

Beta sheet

Alpha helix

Left-handed helix

C f i l


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Conformational space

How many conformations are there?

Sample , torsion in 10 degree units

36 states for each torsion

For a 100-residue chain we get:

362 states per residue

(362

)100

=36200

10308

states for the chain Only one is the native structure

L i h l d


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Levinthals paradox

But proteins obey the laws ofthermodynamics!

Structure must be that with the lowest

free energy

Levinthal: how can a protein do that?

We just saw that there are too manystates! Levinthals paradox


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B.Robson 1999

A f ldi d i


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Answer: folding dynamics

The answer lies in the dynamics of how

proteins fold We need to know more about protein

structure

CD S t


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CD Spectroscopy

Circular dichroism - chirality of amino acids will

rotate polarized light

Amount depends on the environment

Cheap, fast, simple, no sequence resolution

N l M ti R


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Nuclear Magnetic Resonance Environment will shift frequency of

nuclearspin resonance - chemical shifts

More complex than CD, but sequence

resolved

P t i t t


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Protein structure

Max Perutz & Hemoglobin

First X-raystructureTook 22 years...


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Kv1.2 ion channel

Large protein, 25k atoms(Rod MacKinnon)

Hierarchical structure:

Amino acid sequence

Secondary structure(sheets, helices)

Tertiary structure (1 chain)

Quaternary structure(more chains)

P t i t t


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Protein structure

FABP(Fatty acid binding protein)

NMR structure:

Multipleconformations

S d t t


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Secondary structure

Local structure is very ordered

Helices

Sheets

Turns

Stable building blocks

Paired hydrogen bonds Good local packing

No interference of side chains

H li


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Helices

Naturally occurring amino acid

helices are right-handed

Nomenclature: NM-helix

Residue i h-bonds to i+N M atoms per helical turn

310 helix

413 () helix - most common!

Other (very rare) forms: 27 and 516 ()helix

Heli e amples


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Helix examples

310 helix helix

helix

The -helix is the mostrelaxed of the helical

structures

Helices on the Ramachandran plot


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Helices on the Ramachandran plot

-helices occupy favorable part of diagram3.6 residues per turn (100 degrees per residue)

27

310

left

Helix dipole


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Helix dipole

Peptide dipoles parallel, from N to Cterminus

Strong dipole - important in some ionchannels!

Partial + charge at N, partial - charge at C

+-

Partial charges


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Partial charges

-0.82-0.82

-0.82

+0.41

+0.41 +0.41

+0.41

+0.41

+0.41

Effective average charge + location can

be different from unit charge:

Helix dipoles


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Helix dipoles

In helix: effective dipole = sum of amino

acid dipole contributions.

Beta sheets


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Beta sheets

Antiparallel sheets Parallel sheets

Sheet properties


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Sheet properties

Extended chains

H-bonds between, not

inside individual chains

Pleated sheets

Slightly twisted


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Pauling, Corey (and partly Branson) - 1951

The protein papers (8 papers in PNAS vol 37)

http://www.pnas.org/misc/classics1.shtml

Tight turns in sheets
http://www.pnas.org/misc/classics1.shtmlhttp://www.pnas.org/misc/classics1.shtml


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Tight turns in sheets

Venkatachalam, 1968 (models)Simple steric repulsion

Type (i+1) (i+1) (i+2) (i+2)

I -60 -30 -90 0

I 60 30 90 0

II -60 120 80 0

II 60 -120 -80 0

IV -61 10 -53 17

VIa1 -60 120 -90 0

VIa2 -120 120 -60 0

VIb -135 135 -75 160

VIII -60 -30 -120 120

Type I Type II

Helices vs Sheets


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Helices vs. Sheets

Helices:

Local h-bonds

Gradual (but fast) growth

Low initiation barrier Sheets:

Non-local h-bonds

Collective interactions; all-or-nothing

High initiation barrier - very slow

formation

Amino acid properties


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All amino acids are not equal Proline is very rare in alpha helices

Glycine is common in tight turns

Some residues common at helix ends

Differences inside/surface of proteins

What is the cause of these differences,and can it be useful?



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Name 3-letter code 1-letter code Abundance G solvationGl cine GLY G 6.89%

Alanine ALA A 7.34% 1.94

Proline PRO P 5.00%Glutamic acid GLU E 6.22% -79.12

Glutamine GLN Q 3.96% -9.38

As artic acid ASP D 5.12% -80.65

As ara ine ASN N 4.57% -9.70

Serine SER S 7.38% -5.06

Histidine HIS H 2.26% -10.27/-64.13

L sine LYS K 5.81% -69.24

Ar inine ARG R 5.20% ~ -60

Threonine THR T 5.85% -4.88

Valine VAL V 6.48% 1.99

Isoleucine ILE I 5.76% 2.15

Leucine LEU L 9.36% 2.28

Metionine MET M 2.32% -1.48Phen lalanine PHE F 4.12% -0.76

T rosine TYR Y 3.25% -6.11

C steine CYS C 1.76% -1.24

Tr to han TRP W 1.34% -5.88

GLU or GLN GLX Z = E OR Q

ASP or ASN ASX B = D OR NAn amino acid XXX X kcal/mol




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Proline


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Proline

Proline: Cannot form hydrogen bonds, bulky

side-chain with two carbons connectedtothe backbone nitrogen atom

N-terminus of alpha helices

Turns Normally not inside

helices/sheets

Glycine + Alanine


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Glycine + Alanine

Glycine

No side chain means no clashes

Flexible ramachandran map

No entropic stabilization

Common in turns (flexible)

Alanine

Methyl side chain

Slight helix preference, but sheet ok

Hydrophobic residues


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Hydrophobic residues

Normally prefer beta sheets

Side chains protrude onalternating sides

More room for bulkyside chains (often h-phobic)

In particular residueswith two carbons

Polar + charged residues


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Polar + charged residues Polar:

Prefers turn/loop regions

H-bonds to both water andthe polypeptide chain

Charged:

Occurs on surface, in active sites

Negative charges stabilize helix N-terminus

Positive charges stabilize helix C-

terminus

Helix capping


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Helix capping

+ - ARGLYSHIS

ASPGLU

Charged residues act as caps for the helixdipole, which stabilizes both the helix andthe charged residue in that position


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The protonation state ofcharged/polar amino acidsdepends on the current pH

AA pH 7 pKa

GLU -1 4.3

ASP -1 3.9

HIS 0 or +1 6.5

LYS +1 10.5

ARG +1 12.5TYR 0 10.1

CYS 0 9.2Tricky;ver

yclosetoneutralpH

Depends

onenvironm

enttoo

Summary


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Summary

Amino acid properties Protein structure - aa backbone +

sidechains

More about proteins next lecture!

If needed, read up on protein structure inIntroduction to Protein Structure

Lab on proteins & molecular graphics intwo weeks (Nov 17)

Next Lecture: Wednesday afternoon

molecular_modeling

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