Molecular simulations of polypeptides under
confinement
CHEN633: Final ProjectRafael Callejas-Tovar
Artie McFerrin Department of Chemical EngineeringTexas A&M University
Instructor: Prof. Perla B. Balbuena
Outline
1. The protein folding problem2. Protein-folding dynamics and
molecular simulations3. Paper: “Molecular dynamics
simulations of poly(alanine) peptides”
Some definitions
• Amine group +
• Carboxylic acid group +
• Side-chain Amino acid
• Chain of amino acids
• Peptide bonds
Polypeptide • One or more
polypeptides
Protein
http://en.wikipedia.org/wiki/Protein
What is protein folding?
• Process by which a polypeptide folds into its characteristic and functional 3-D structure from a random coil
http://en.wikipedia.org/wiki/Protein_folding
Unfolded polypeptide: No
3-D structure
Native state (thermodynamically
stable)
Amino acid
interactions
What is protein folding?
• Correct 3-D structure is essential to function
• Failure to fold into native structure produces inactive proteins that are usually toxic – Several neurodegenerative and other
diseases caused by unfolded proteins –Many allergies are caused by the folding
of the proteins
http://en.wikipedia.org/wiki/Protein_folding
The protein folding problem
• Anfinsen’s Thermodynamic Hypothesis– Nobel Prize in Chemistry (1972)
Christian B. Anfinsen– Native structure:• Depends only on amino acid sequence and
conditions of solution• DO NOT depend on the kinetic folding route
Dill, K.A., Ozkan, S.B., Shell, M.S., and Weikl, T.R., The Protein Folding Problem. Annual Review of Biophysics, 2008. 37(1): p. 289-316.http://en.wikipedia.org/wiki/Anfinsen%27s_dogmahttp://en.wikipedia.org/wiki/Christian_B._Anfinsen
The protein folding problem
• What is the folding code?• What is the folding mechanism?• Can we predict the native structure
of a protein from its amino acid sequence?
Dill, K.A., Ozkan, S.B., Shell, M.S., and Weikl, T.R., The Protein Folding Problem. Annual Review of Biophysics, 2008. 37(1): p. 289-316.http://techglimpse.com/index.php/ibms-blue-gene-exploring-protein-folding-mystery.php
Protein structure prediction: Levinthal's paradox
• Number of possible conformations available to a given protein is astronomically large– Even a small protein of 100 residues would
require more time than the universe has existed to explore all possible conformations (1026 seconds) and choose the appropriate one
• The “paradox”: Most small proteins fold spontaneously on a millisecond or even microsecond time scale
Dill, K.A., Ozkan, S.B., Shell, M.S., and Weikl, T.R., The Protein Folding Problem. Annual Review of Biophysics, 2008. 37(1): p. 289-316.http://en.wikipedia.org/wiki/Levinthal%27s_paradox
Protein-folding dynamics and molecular simulations
• Computer-based molecular minimization methods applied since 1960
• Molecular dynamics with high parallelized codes–More global and less detailed
information– Physics-based reduced models– All-atom models Scheraga, H.A., Khalili, M., and Liwo, A., Protein-Folding Dynamics: Overview of Molecular Simulation Techniques.
Annual Review of Physical Chemistry, 2007. 58(1): p. 57-83. http://bits.blogs.nytimes.com/2007/11/12/ibm-blue-gene-still-the-fastest-computer/
“Molecular dynamics simulations of poly(alanine) peptides”
Palenčár, P. and Bleha, T., Journal of Molecular Modeling, 17(9): p. 2367-2374 (2011)
What is the objective?
• Exploring the folding of poly(alanine) (PA) peptides
Secondary structures
• (Ala)n of intermediate lengths
Structure and confinement
• How the helical structure of a PA molecule is affected due to confinement?
Why is this important?
• Poly(alanine): best-known representative of the polypeptide group– Its folding is of considerable interest, as
alanine (Ala) is generally viewed as the most helix-stabilizing amino acid residue
How did they do it?
• All-atoms molecular dynamics simulations– NVT without solvent and AMBER-99φ
force-field
Palenčár, P. and Bleha, T., Folding of Polyalanine into Helical Hairpins. Macromolecular Theory and Simulations, 2010. 19(8-9): p. 488-495.
Free &confine
d
Acetyl & methyl amide for charge
neutralityGetting initial
configurations
(…about the α-helix)
• Right-handed coiled or spiral conformation– Every backbone N-H group donates a H
bond to the backbone C=O group of the amino acid four residues earlier
http://en.wikipedia.org/wiki/Alpha_helix
What did they get?
ConversionStraight α-helix
α-hairpins
Melting/cooling curve
Incr
eas
e
3 10 PPIIH H H H
Chain length and confinement effects
Abundance of structures with NH segments at 303K
• (Ala)40: – Straight helices
• (Ala)45:– Two-leg (2L) α-hairpins
prevails
• (Ala)60:– No straight helices– two-leg (2L) α-hairpins
prevails
• Confined (Ala)60: – three-leg (3L) α-hairpins
prevails
Chain length and confinement effects
Abundance of structures with NH segments at 303K
• (Ala)40: – Straight helices
• (Ala)45:– Two-leg (2L) α-hairpins
prevails
• (Ala)60:– No straight helices– two-leg (2L) α-hairpins
prevails
• Confined (Ala)60: – three-leg (3L) α-hairpins
prevails
Stabilization energies at 303K
• Stability of folded structures decreases with the number of folds
Shape of the PA chains
2
2
12 rod-like objects
~ 6 random coils
1 compact objectsg
R
R
• Unconfined: Random at high T
• Shape is modified greatly by chain length
• Shape transition caused by confinement
Effect of the confinement on the energy contributions
Unconfined Confinement
PA peptide on a cubic cavity(Ala)60 chains confined to a cube
Hairpin-like structures (cube 0.39)
Moderateconfineme
nt
Degree of confinement
What are their conclusions?
• Conformational structures– Highly sensitive to chain length
• Under confinement–Multi-legs hairpins observed– Considerable reduction on overall helicity
of PA molecules– Helical chains transform into compact
structures resembling the organization of integral membrane proteins (stacked α helices)
References
• Dill, K.A., Ozkan, S.B., Shell, M.S., and Weikl, T.R., The Protein Folding Problem. Annual Review of Biophysics, 2008. 37(1): p. 289-316. http://dx.doi.org/10.1146/annurev.biophys.37.092707.153558
• Scheraga, H.A., Khalili, M., and Liwo, A., Protein-Folding Dynamics: Overview of Molecular Simulation Techniques. Annual Review of Physical Chemistry, 2007. 58(1): p. 57-83. http://dx.doi.org/10.1146/annurev.physchem.58.032806.104614
References
• Palenčár, P. and Bleha, T., Molecular dynamics simulations of the folding of poly(alanine) peptides. Journal of Molecular Modeling, 2011. 17(9): p. 2367-2374. http://dx.doi.org/10.1007/s00894-011-0997-4
• Palenčár, P. and Bleha, T., Folding of Polyalanine into Helical Hairpins. Macromolecular Theory and Simulations, 2010. 19(8-9): p. 488-495. http://dx.doi.org/10.1002/mats.201000034
References
• Sikorski, A. and Romiszowski, P., Computer simulation of polypeptides in a confinement. Journal of Molecular Modeling, 2007. 13(2): p. 327-333. http://dx.doi.org/10.1007/s00894-006-0147-6
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