Transcript Centre of Excellence for Multi

Modeling and Understanding Complex Biomolecular
Systems and Processes.
Application in Nanosciences, Biotechnology and
Biomedicine
Bogdan Lesyng
ICM and Faculty of Physiscs, Warsaw University
(http://www.icm.edu.pl/~lesyng/)
and
European Centre of Excellence for
Multiscale Biomolecular Modelling,
Bioinformatics and Applications
Trento, 16-17 December, 2004
(http://www.icm.edu.pl/mamba)
Sequences
at the protein &
nucleic acids levels
1
11
21
31
41
51
RPDFCLEPPY
TGPCKARIIR
YFYNAKAGLC
QTFVYGGCRA
KRNNFKSAED
CMRTCGGA
Metabolic
pathways &
signalling
3D & electronic
structure
Function
Dynamics,
classical and/or
quantum one in
the real
molecular
environment
10
20
30
40
50
58
Sub-cellular
structures & processes
Cell(s),
structure(s)
&
functions
In our organisms
we have ~ 103
protein kinases
and phosphatases
which
phosphorylate/
dephosphorylate
other proteins
activating or
disactivating
them.
These are
controllers
of most of
methabolic
pathways.
A Protein Kinase Molecule with ATP (catalytic domain)
Information,
conference on
”Inhibitors of
Protein Kinases”,
and workshops on
”Molecular
Recognition
Processes”
June 26-30, 2005
Warsaw
http://www.icm.edu.pl/
ipk2005/
Designing inhibitors
Limitations of conventional bioinformatics approaches
in structure predicion
•Homology based structure prediction methods are
effective for those families of proteins which
crystallize. They fail, for example, for membrane
proteins.
•Methods developed for proteins fail for nucleic acids.
Folding of nucleic acids, like folding of single-stranded
RNA, could be even more important than protein
folding (to learn what is the role of noncoding regions)
Multi-scale modeling. Classes of models
Microscopic models
Mesoscopic models
Recently I participated in the Robert Welch Foundation Conference on
„Chemistry of Self-Organizing Hybrid Materials”, Houston, Oct.25- 26,
2004. Selected topics below:
•
Biologically Active Self-Assembling Peptide Nanotubes
•
Conditional Control of BiopolymerSelf Assembly and Activity
•
Electroactive Functional Polymers and Nanocomposites
•
Nanotechnology : Carbon Nanotubes, Nanomachines and
Molecular Computers
•
Using Self-Assembly to Create Electronic Materials
Objects and processes listed above require, amongst others, the knowledge
of effective iteraction potentials – refer to the following port of my talk.
Microscopic generators of the potential
energy function
• AVB
• AVB/GROMOS
•
•
•
•
SCC-DFTB
- (quantum)
SCC-DFTB/GROMOS - (quantum-classical)
SCC-DFTB/CHARMM - (quantum -classical)
....
Dynamics
•
•
•
•
– (quantum)
- (quantum-classical)
MD (classical)
QD (quantum)
QCMD (quantum-classical)
....
Mesoscopic potential energy functions
•Poisson-Boltzmann (PB)
•Generalized Born (GB)
•....
SCC-DFTB Method
(Self Consistent Charge Density Functional Based Tight Binding Method,
SCC DFTB, Frauenheim et al. Phys Stat. Sol. 217, 41, 2000)
basic DFT concepts:
total electron
density
1-electron orbitals
1-electron
Hamiltonian
(Kohn-Sham equation)
Dipole moments in Debyes
6
Mulliken
5
CM3
Calculated
4
3
2
1
0
0
1
2
3
Experimental
4
5
6
New generation of charges capable reproducing
electrostatic properties, in particular molecular
dipole moments.
J.Li, T.Zhu, C.Cramer, D.Truhlar, J. Phys. Chem. A, 102, 1821(1998)
CM3/SCC-DFTB charges
J.A. Kalinowski, B.Lesyng, J.D. Thompson, Ch.J. Cramer, D.G. Truhlar, Class
IV Charge Model for the Self-Consistent Charge Density-Functional TightBinding Method, J. Phys. Chem. A, 108, 2545-2549 (2004)
Mesoscopic models of the
molecular electrostatic
energy
Poisson-Boltzmann (PB) method
 
 
  2 
rrqkr rk rr r
k
2
2
e
 I
2
kT
Debye-Huckel screening
parameter, I-ionic strength
r i qi
solving on a grid, or
with final elements
extr    qi ni (r)
i

  q ( r ) 

n ( r )  n0 exp  

kT 

external ionic density
in thermodynamic
equilibrium
Looking for very fast algorithms to compute the
mean-field (mesoscopic) electrostatic energy.
Born models:
•M.Born, Z.Phys., 1,45(1920)
•R.Constanciel and R.Contreas, Theor.Chim.Acta,
65,111(1984)
•W.C.Still, A.Tempczyk,R.C.Hawlely,T.Hendrikson,
J.Am.Chem.Soc.,112,6127(1990)
•D.Bashford, D.Case, Annu.Rev.Phys.Chem., 51,129(2000)
If we know, so called Born-radii of atoms, we can very
quickly compute the electrostatic energy. A Born radius is
a geometrical property !
Born radii
and
Van der Waals radii
Molecular area
The same type of atoms are characterized by
different Born radii. Their values depend on
geometry of the molecular system, and on
localization of the atoms in the system (geometrical
property). The Born radii are large inside, and are
close to VdW radii on the surface.
Expressions for Born radii
1
1

Ri 4
1 3
d r
4

r
so lven t
Coulomb Field appr. (I)
A.Onufriev, D.Bashford,D.Case, J.Phys.Chem.B, 104,3712-3720(2000)
1  3
 
Ri  4
1 3
d r 
6

r
solvent

1
3
Kirkwood Model (II)
T.Grycuk, J.Chem.Phys, 119, 4817-4826(2003)
Ri  
1
 3 ex 
 A7
Co A4  C1 
 3 ex  2 in 
D
E
 ex  1
(III)
 1
1
A7   4 
 4RVdW 4
1 3
in r 7 d r 
1
4
M.Feig, W.Im, C.L.Brooks, J.Chem.Phys.,120,903-911(2004)
1  n3
1 3


d r 
n

Ri  4 so lven t r

1
n 3
n
4.32
  so lu te
 033


so lv


M.Wojciechowski, B.Lesyng, J.Phys Chem, in press
0. 3
(IV)
Ratio of the GB solvation enery to the Kirkwood solvation energy
There are non-solved problems
(like hydrophobic potentials),
but it looks like
in the near future we will have
a new generation of effective
(mean-field, mesoscopic) molecular
interaction potentials, which can be
applied to
structure prediction problems
(regardless of the type of biopolymers !)
or ligand – biomolecule interactions.
Conclusions:
•
An integrated approach, using bioinformatics and multiscale-biomolecular
modelling methods, allows to much better
understand complex biomolecular
structures and processes (important
element of the e-science strategy).
•
This influences positively development of
practical applications, such as structure
prediction, molecular design, including
drug design, or biotechnological and
biomedical solutions and strategies.
•
Integration of bioinformatics, chemical
and physical approaches require, however,
new interdisciplinary educational
programs. In particular, coupling of higher
education and interdisciplinary research is
highly required for high-quality science,
emerging technologies and effective
economy.
•
E-science platforms should be based on
novel WEB and GRID technologies.
Acknowledgements:
PhD students:
Jarek Kalinowski
Piotr Kmieć
Magda Gruziel
Michał Wojciechowski
Collaboration:
Prof. T. Frauenheim
Dr. M. Elstner
SCC-DFTB, University of Paderborn, Germany
Prof. D. Truhlar
Dr. J. Thompson
Dr. C. Cramer
CM3-charges, Minnesota Solvation Data Base
University of Minnesota, USA
Prof. J.A.McCammon
Titration of proteins
University of California at San Diego, USA
Studies supported in part by ”European CoE for Multiscale Biomolecular Modelling,
Bioinformatics and Applications” , ICM, Warsaw University.