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Basics

Molecular Modeling, lecture 1

The course
• Biomolecular structure • Formation • Interaction • Sequence ➛ structure ➛ function • Mechanics of biomolecules • Modelling & simulation methods • Analyzing computer simulation results

Book

Andrew R. Leach Molecular Modelling - Principles and Applications, 2nd edition Prentice Hall 2001, ISBN 0582382106

Practicalities
• Lecturers: Berk Hess (hess@cbr.su.se) Björn Wallner (bjorn@cbr.su.se) • Lab exercises: Samuel Murail (samuel.murail@cbr.su.se) Torben Brömstrup (torbenb@cbr.su.se) • Lab reports: due one week after each exercise

Schedule • Tentitative schedule is up at: http://www.se/Teaching/Courses/ Molecular_Modeling • exam: Friday December 17.su. 9:00-14:00 .dbb.

Why computer simulations? • Two primary roles: • ‘Numerical experiments’ needs accuracy • Model testing needs reductionism • Computers are fast enough for numerical experiments • Most models are too complicated for purely theoretical reasoning Allen&Tildesley .

etc. mechanisms) • Molecular scale: quantum-mechanical .) • Dynamic properties (rates.Molecular modeling • Molecular modeling in biomolecules: mostly numerical experiments • Aim: prediction of macroscopic properties • Ensemble averages/static properties (binding constants.

Time scales Biological Experiments 10-15s 10-12s 10-9s 10-6s 10-3s 100s 103s Coarse-grained models (Whole proteins) Molecular dynamics (Atomic detail) QM simulations (Electrons) .

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 classically anyway: need to coarse-grain! .

Atomic-scale simulations • Coarse grained: needs ‘force fields’ from quantum mechanical simulations • Good description level for understanding individual proteins & simple interactions • Can simulate protein dynamics up to ~10μs .

Protein structure .

Protein dynamics .

4 kBT • Completely determines protein structure: responsible for hydrophobicity. or 8.Water • Most ubiquitous molecule in life: water • Forms hydrogen bonds • Strong interaction: ~20 kJ/mol. .

Hydrophobicity • Cavities in water disfavored: • small cavities disrupt hydrogen bond network • big cavities form surfaces: hydrophobic effect .

Natural amino acids .

χ2.Peptide structure • Backbone degrees of freedom: • Peptide (Ω) bond (trans/cis for Pro) • Φ (C-N-CA-C) • Ψ (N-CA-C-N) torsions • Side chain degrees of freedom: • χ1.χ3 torsions .

Peptide structure Beta sheet Left-handed helix Alpha helix .

Ψ torsion in 10 degree units • 36 ‘states’ for each torsion • For a 100-residue chain we get: • 362 states per residue 2 100 200 308 • (36 ) =36 ≈10 states for the chain • Only one is the native structure .Conformational space • How many conformations are there? • Sample Φ.

Levinthal’s paradox • But proteins obey the laws of thermodynamics! • Structure must be that with the lowest free energy • Levinthal: how can a protein do that? • We just saw that there are too many states! Levinthal’s paradox .

Robson 1999 .B.

Answer: folding dynamics • The answer lies in the dynamics of how proteins fold • We need to know more about protein structure .

no sequence resolution .chirality of amino acids will rotate polarized light • Amount depends on the environment • Cheap.CD Spectroscopy • Circular dichroism . fast. simple.

Nuclear Magnetic Resonance • Environment will shift frequency of nuclear spin resonance . but sequence resolved .‘chemical shifts’ • More complex than CD.

Protein structure First X-ray structure Took 22 years. Max Perutz & Hemoglobin ...

25k atoms (Rod MacKinnon) Hierarchical structure: • Amino acid sequence • Secondary structure (sheets. helices) • Tertiary structure (1 chain) • Quaternary structure (more chains) .Kv1.2 ion channel Large protein.

Protein structure FABP (Fatty acid binding protein) NMR structure: Multiple conformations .

Secondary structure • Local structure is very ordered • Helices • Sheets • Turns • Stable building blocks • Paired hydrogen bonds • Good local packing • No interference of side chains .

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 (α) helix .most common! • Other (very rare) forms: 27 and 516 (π) helix .

Helix examples The α-helix is the most relaxed of the helical structures α helix 310 helix π helix .

Helices on the Ramachandran plot 27 αleft α 310 α-helices occupy favorable part of diagram 3.6 residues per turn (100 degrees per residue) .

partial . from N to C terminus • Strong dipole .charge at C .important in some ion channels! • Partial + charge at N.Helix dipole +δ -δ • Peptide dipoles parallel.

82 +0.Partial charges • Effective average charge + location can be different from unit charge: +0.41 +0.41 -0.41 .41 -0.82 +0.41 -0.41 +0.82 +0.

.Helix dipoles • In helix: effective dipole = sum of amino acid dipole contributions.

Beta sheets Antiparallel sheets Parallel sheets .

Sheet properties • Extended chains • H-bonds between. not inside individual chains • Pleated sheets • Slightly twisted .

• Pauling.1951 • “The protein papers” (8 papers in PNAS vol 37) • http://www. Corey (and partly Branson) .org/misc/classics1.shtml .pnas.

Tight turns in sheets Venkatachalam. 1968 (models) Simple steric repulsion Type I I’ II II’ IV VIa1 VIa2 VIb VIII φ(i+1) -60 60 -60 60 -61 -60 -120 -135 -60 ψ(i+1) -30 30 120 -120 10 120 120 135 -30 φ(i+2) -90 90 80 -80 -53 -90 -60 -75 -120 ψ(i+2) 0 0 0 0 17 0 0 160 120 Type I Type II .

very slow formation . 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 .Helices vs.

and can it be useful? .Amino acid properties • 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.

24 ~ -60 -4.27/-64.76 -6.20% 5.Amino acid properties Name Glycine Alanine Proline Glutamic acid Glutamine Aspartic acid Asparagine Serine Histidine Lysine Arginine Threonine Valine Isoleucine Leucine Metionine Phenylalanine Tyrosine Cysteine Tryptophan GLU or GLN ASP or ASN Any amino acid 3-letter code GLY ALA PRO GLU GLN ASP ASN SER HIS LYS ARG THR VAL ILE LEU MET PHE TYR CYS TRP GLX ASX XXX 1-letter code G A P E Q D N S H K R T V I L M F Y C W Z ( = E OR Q ) B ( = D OR N ) X Abundance 6.25% 1.38 -80.85% 6.65 -9.15 2.32% 4.24 -5.89% 7.36% 2.96% 5.12% 3.22% 3.28 -1.00% 6.13 -69.34% 5.57% 7.06 -10.76% 1.99 2.94 -79.88 1.81% 5.34% ΔG solvation 1.48 -0.76% 9.88 (kcal/mol) .26% 5.48% 5.38% 2.12% 4.11 -1.70 -5.12 -9.

Amino acid properties .

bulky side-chain with two carbons connected to the backbone nitrogen atom • N-terminus of alpha helices • Turns • Normally not inside helices/sheets .Proline • Proline: • Cannot form hydrogen bonds.

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 • Normally prefer beta sheets • Side chains protrude on alternating sides • More room for bulky side chains (often h-phobic) • In particular residues with two γ carbons .

Polar + charged residues • Polar: • Prefers turn/loop regions • H-bonds to both water and the polypeptide chain • Charged: • Occurs on surface. in active sites • Negative charges stabilize helix Nterminus • Positive charges stabilize helix Cterminus .

Helix capping +δ -δ ARG LYS HIS ASP GLU Charged residues act as ‘caps’ for the helix dipole. which stabilizes both the helix and the charged residue in that position .

very close to neutral pH Depends on environment too charged/polar amino acids depends on the current pH .3 3.5 10.•The protonation state of AA GLU ASP HIS LYS ARG TYR CYS -1 -1 0 or +1 +1 +1 0 0 pH 7 charge pKa 4.5 12.2 Tricky.1 9.9 6.5 10.

read up on protein structure in “Introduction to Protein Structure” • Lab on proteins & molecular graphics in two weeks (Nov 17) • Next Lecture: Wednesday afternoon .aa backbone + sidechains • More about proteins next lecture! • If needed.Summary • Amino acid properties • Protein structure .