Simulations of the folding and aggregation of peptides, proteins and lipids. BRISBANE School of Molecular and Microbial Sciences (SMMS) Chemistry Building (#68) University of Queensland Brisbane, QLD 4072, Australia Email [email protected]Phone: +61-7-33469922 FAX: +61-7-33654623 Centre Secr: +61-7-33653975 GRONINGEN Lab. of Biophysical Chemistry University of Groni Nijenborgh 4 email 9747 AG GRONINGEN The Netherla tel +31.50.3634457 fax: +31.50.3634800 tel secr: +31.50.3634323 email:[email protected]secr: [email protected]http://md.chem.rug.nl Alan E. Mark Herman Berendsen Siewert-Jan Marrink
15
Embed
Simulations of the folding and aggregation of peptides, proteins and lipids. BRISBANE School of Molecular and Microbial Sciences (SMMS) Chemistry Building.
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
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
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.
Daura, X., van Gunsteren, W. F. and Mark, A. E. (1999) Proteins: Struct. Funct. Genet. 34, 269-280.
Folding Pathways
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
Density Evolution Showing the Generation of Orderde