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Simulations of the folding and aggregation of peptides, proteins and lipids.

Simulations of the folding and aggregation of peptides, proteins and lipids.

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Simulations of the folding and aggregation of peptides, proteins and lipids.

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  1. Simulations of the folding and aggregation of peptides, proteins and lipids. BRISBANE School of Molecular and Microbial Sciences (SMMS)Chemistry Building (#68)University of QueenslandBrisbane, QLD 4072,AustraliaEmail a.mark@uq.edu.auPhone: +61-7-33469922 FAX: +61-7-33654623Centre Secr: +61-7-33653975GRONINGEN Lab. of Biophysical Chemistry University of Groningen Nijenborgh 4 email 9747 AG GRONINGEN The Netherlands tel +31.50.3634457fax: +31.50.3634800 tel secr: +31.50.3634323email:a.e.mark@rug.nl secr: mdsecr@fmns.rug.nl http://md.chem.rug.nl Alan E. Mark Herman Berendsen Siewert-Jan Marrink

  2. Peptide folding and assembly: • Our best example of peptide folding to date is a the beta-hexapeptide shown • on the following slides (solvent Methanol). • This system is fully reversible. • We have simulations of this and other systems to > 200ns at temperatures • from 180 -> to 450K. • We have replica exchange simulations of a slightly modified system • showing 1000’s of individual folding events. • As far as we can determine our modified system approaches full • convergence in 200-400 ns. • 5. Trajectories are available.

  3. -Peptides • -amino-acids (additional backbone carbon) • Stable 2nd structure. • Non-degradable peptide mimetics • (e.g. highly selective somatastatin analogue) -Heptapeptide (M) 31-helix in MeOH at 298 K (left-handed) D. Seebach, B. Jaun + coworkers organic chem ETH-Zurich Daura, X., Bernhard, J., Seebach, D., van Gunsteren, W. F. and Mark, A. E. (1998) J. Mol. Biol. 280, 925-932.

  4. -Heptapeptide, 340 K unfold fold unfold fold unfold fold unfold

  5. Starting structure -Heptapeptide, 360 K Gfolding = -RT ln (folded/unfolded)

  6. Predict Probability of Individual Microstates in Solution G=0 kJ/mol G=~6 kJ/mol G=~8 kJ/mol G=~9 kJ/mol G=~9 kJ/mol Daura, X., van Gunsteren, W. F. and Mark, A. E. (1999) Proteins: Struct. Funct. Genet. 34, 269-280.

  7. Folding Pathways

  8. Simulations of peptide folding As part of our program we are looking a range of larger peptides. So far getting reversible folding from random starting structures has proved difficult for systems > 20 a.a. In particular we are investigating a series of related helical peptides (~20 a.a.) with fast folding kinetics AP A5(A3RA)3A YGA Ac-YG(AKA3)2AG-NH2 YGG Ac-YGG(KA4)3K-NH2 So far results are limited but we have seen reversible transitions. An example is given below.

  9. AP A5(A3RA)3A Ref: Lednev I. K. et al. J. Am. Chem. Soc. 1999, 121, 8074-8086. • A 21 amino acid, mainly alanine, α-helical peptide (AP). • The folding/unfolding activating barriers based on an nanosecond UV resonance Raman study. • ~8 kcal/mol activation barrier; reciprocal rate constant ~240±60 ns at 37 °C (310 K). MD simulation start from the α-helix structure The GROMOS 45A3 force field was adopted

  10. β-Sheet β-Bridge Bend Turn α-helix 5-Helix 3-Helix Coil The secondary structure as a function of time shows one refolding transition in 100ns. Secondary structure Residue Time (ps)

  11. C-ter N-ter N-ter N-ter C-ter N-ter C-ter 30 ns 50 ns C-ter 10 ns 0 ns (starting structure) N-ter C-ter N-ter N-ter C-ter C-ter C-ter N-ter N-ter C-ter 85 ns 75 ns 70 ns 80 ns 100 ns

  12. Other peptide systems on which we have simulations showing partial • folding or assemble include: • Various amyloid forming peptides on surfaces. • Betanova (a designed triple stranded peptide) • A series of coiled-coils. • WW domain peptide (~20 a.a. peptide studied by replica exchange) • Several proteins showing recovery from mild denaturing conditions.

  13. Spontaneous Aggregation of Lipids and Surfactants I believe this is one area where complexity analysis should be able to perform well as the systems show spontaneous generation of order. • We have multiple simulations of: • Bilayer formation (course grained and in atomic detail) • Vesicle formation (course grained and in atomic detail) • Phase transitions (course grained and in atomic detail) • Membrane and vesicle fusion. Note: these are highly reproducible collective processes involving 100’s to 1000’s of lipids. A few examples are given below.

  14. Spontaneous assembly of phospholipds into a bilayer A B C 0 ns 0.2 ns 3 ns Ceq C* Deq 25 ns 20 ns 10 ns S.J. Marrink

  15. Density Evolution Showing the Generation of Order density water head groups lipid tails S.J. Marrink

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