View
217
Download
3
Tags:
Embed Size (px)
Citation preview
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,Australia
Email [email protected]: +61-7-33469922 FAX: +61-7-33654623Centre Secr: +61-7-33653975
GRONINGEN Lab. of Biophysical Chemistry University of Groningen Nijenborgh 4 email 9747 AG GRONINGEN The Netherlands
tel +31.50.3634457fax: +31.50.3634800tel secr: +31.50.3634323email:[email protected] secr: [email protected]
http://md.chem.rug.nl
Alan E. Mark Herman BerendsenSiewert-Jan Marrink
Peptide folding and assembly:
Our best example of peptide folding to date is a the beta-hexapeptide shown on the following slides (solvent Methanol).
1. This system is fully reversible. 2. We have simulations of this and other systems to > 200ns at temperatures from 180 -> to 450K.3. We have replica exchange simulations of a slightly modified system
showing 1000’s of individual folding events. 4. As far as we can determine our modified system approaches full
convergence in 200-400 ns. 5. Trajectories are available.
-Peptides
i) -amino-acids (additional backbone carbon)ii) Stable 2nd structure.iii) Non-degradable peptide mimetics
(e.g. highly selective somatastatin analogue)
D. Seebach, B. Jaun + coworkersorganic chem ETH-Zurich
-Heptapeptide (M) 31-helix in MeOH at 298 K
(left-handed)
Daura, X., Bernhard, J., Seebach, D., van Gunsteren, W. F. and Mark, A. E. (1998)
J. Mol. Biol. 280, 925-932.
Predict Probability of Individual Microstates in Solution
G=~6 kJ/mol G=~8 kJ/molG=0 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.
Simulations of peptide folding
As part of our program we are looking a range of larger peptides. So far gettingreversible 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.
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 structureThe GROMOS 45A3 force field was adopted
Coil β-Sheet β-Bridge Bend Turn α-helix 5-Helix 3-HelixTime (ps)
Res
idu
e
Secondary structure
The secondary structure as a function of time shows one refolding transition in 100ns.
N-ter
C-ter
0 ns (starting structure)
N-ter
C-ter
10 ns
N-ter
C-ter
30 ns
C-ter
N-ter
50 ns
N-ter
C-ter
75 ns
N-ter
C-ter
70 ns
N-terC-ter
80 ns
N-ter C-ter
85 ns
N-ter
C-ter
100 ns
Other peptide systems on which we have simulations showing partial folding or assemble include:
1. Various amyloid forming peptides on surfaces.2. Betanova (a designed triple stranded peptide)3. A series of coiled-coils.4. WW domain peptide (~20 a.a. peptide studied by replica exchange)5. Several proteins showing recovery from mild denaturing conditions.
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: 1. Bilayer formation (course grained and in atomic detail)2. Vesicle formation (course grained and in atomic detail)3. Phase transitions (course grained and in atomic detail)4. 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.
S.J. Marrink
A
Ceq
CB
DeqC*
Spontaneous assembly of phospholipds into a bilayer
0 ns 0.2 ns 3 ns
10 ns 20 ns 25 ns