PUMPKIN Ideas
Objectives
Development and application of methods to:
Model the dynamics of domain motion in large
proteins
Incorporate experimental data such as point
mutation results in a protein domain model
Improved understanding of the
structure and function of P-type ATPases
The Time Scale Obstacle
Pump reaction cycle => ms time scale
CG MD => only μs time scale
Even coarser formalism needed!
Implicit Solvent
Nature Letter 2007
Reynwar et al.
Max Planck Institute, Mainz
Protein Domain Model
Sarcoplasmic reticulum Ca2+-ATPase (SERCA)
Chemical Grid
Rigid but soft – use knowledge from SERCA
Lipid model 3 4 5 6
Resolution /Å 13-10 11-8 9-6 7-4
Flexible
Chemical Grid
Every amino acid or functional group has a
degree of hydrophobicity assigned e.g. from 0 – 1
The overall hydrophobicity of the grid-point-area is found
0-0.3 => hydrophilic grid point
0.3-0.7 => both hydrophobic and hydrophilic
0.7-1 => hydrophobic grid point
Electrostatics: The overall charge of the grid-point-area is used?
Special Challenges
Sometimes single waters are relevant...
Typically ions are involved....
Bonds are broken and formed...
Point mutations....
Points / amino acids of known importance...
Build Protocol
Yes AA struct. No
Model ready for
known? simulation
e.g. X-ray pdb
e.g. pdb with
Remove everything coors for Cα Add lipid bilayer and
but the protein. other molecules
Prep protein. such as ions, ATP, water...
No Protocol that tests and
Known
suggests how domains
domains?
could be defined.
Yes Make sure that important
spots have the right
Define domains from resids like e.g. chemistry and modify
D1 8-20, 40-52, ..... manually if necessary.
D2 23-32, 60-84, .....
.........
Generate surface grid for every Assign every grid point
domain and linkers. a chemical class.
Work Plan
Modelling physicist, computer and the
Recruit - studies with AA, CG scientist,current
version of the protein domain model.
mathematician?
Develop a protein domain model and make it
* To increase the understanding of the system
work with the lipid model in a MD framework.
* Refine the protein domain model
To collect data at a higher resolution levels for
improve accuracy
testing and forming the protein domain model
allow for description of various detailed chemistry
*
Together with Birgit’s group proteins with
Generalize model to other
domain motion
Input
Comments to these ideas?
Other ideas for projects?
Expectations?