2010 Annual Report - Institute for Molecular Bioscience - University ...

63 imb researchers: joint appointments
ALAN E. MARK
MOLECULAR DYNAMICS OF BIOMOLECULAR
SYSTEMS
surface receptors. In particular, we are
investigating how the binding of human
growth hormone to the extra-cellular
growth hormone receptor is coupled to
structural changes within the cell. We are
also investigating the mechanism by which
the E or envelope proteins of the Dengue
and Ebola viruses facilitate the entry of
these viruses into cells.
THE GROUP CONCENTRATES ON
modelling the structural and dynamic
properties of biopolymers such as proteins,
nucleic acids and lipid aggregates. In
particular, we use computer simulations to
understand and predict the macroscopic
(experimentally observable) behaviour of
complex biomolecular systems based
on the interactions between atoms. We
develop the software, atomic force fields
and theoretical models needed to address
a range of fundamental questions.
First, how do proteins fold Understanding
how proteins fold is one of the grand
challenges of modern biology and a critical
test of our ability to accurately predict
interactions in protein systems. The failure
of proteins to fold correctly is also linked to
a range of debilitative diseases including
Alzheimer’s Disease, BSE and some
forms of Type II diabetes where misfolded
proteins form destructive aggregates
called amyloid fibrils. Dramatic progress
is being made in the de novo folding of
small peptides and the refinement of larger
proteins. Research on folding is conducted
at multiple levels. Small model systems are
used to refine force fields and simulation
techniques. On a larger scale we are
simulating how multiple copies of certain
peptides aggregate in order to understand
how amyloid fibrils form.
Second, how do cell surface receptors
transmit a signal through the cell
membrane Receptor proteins on the
surface of cells play a vital role in cellular
communication. However, little is known
in regard to the mechanism by which the
binding of a molecule to an extracellular
receptor transfers a signal across the
cell membrane or even how changes in
the environment can activate certain cell
Third, how do membrane-protein
complexes assemble Cell membranes
are the archetypal self-organised
supramolecular structure. In addition to
being of critical importance in structural
biology, membrane-protein complexes
are also prime therapeutic targets. Using
simulations, we are investigating the
assembly of functional structures such as
the assembly of anti-microbial peptides
into transmembrane pores. This is being
used to understand the mechanism
by which larger complexes form in
heterogeneous environments as well as to
understand in detail how smaller antibiotics
such as vancomycin recognise membrane
targets.
RESEARCH PROJECTS
• Peptide folding and assembly
• Mechanism of action of antimicrobial
peptides.
• The nucleation and growth of amyloid
fibrils
• Mechanism of activation of type 1
cytokine receptors
KEY PUBLICATIONS
Malde, A., and Mark, A.E. (2010).
Challenges in the determination of the
binding modes of non-standard ligands
in X-ray crystal complexes. Journal of
Computer-Aided Moecular Design 25:
1-12.
Poger, D., and Mark, A. E. (2010). Turning
the growth hormone receptor on: Direct
evidence that hormone binding induces
subunit rotation. Proteins: Structure,
Function, and Bioinformatics. 7: 1163-
1174.
Periole, X., Rampioni, A., Vendruscolo,
M., and Mark, A.E. (2009). Factors that
affect the degree of twist in b-sheet
structures: A molecular dynamics
simulation study of a cross-ß filament
of the GNNQQNY peptide. Journal of
Physical Chemistry B 113: 1728-1737.
The interaction of the peptide D-ala-D-ala
(solid representation) with the antibiotic
vancomycin. The red spheres indicate the
distribution of structural waters observed
during the simulations.
Rotation of the extracellular domains of
the growth hormone receptor associated
with activation by growth hormone. A
superposition of the hormone free form
obtained from the simulations (green and
red) on to the hormone bound (activated)
conformation (yellow)
Yesylevskyy, S., Marrink, S.J., and Mark,
A. E. (2009). Alternative mechanisms
for the interaction of the cell-penetrating
peptides Penetratin and the TAT peptide
with lipid bilayers. Biophysical Journal 97:
40-49.
van Gunsteren, W.F., Dolenc, J., and
Mark, A.E. (2008). Molecular simulation
as an aid to experimentalists. Current
Opinion in Structural Biology 18: 149-153.
LAB MEMBERS
Research Officers: Dr David Poger, Dr
Alpesh Malde, Dr Megan O’Mara, Dr
Mortiz Wigner
PhD Students: Daniela Mueller, Ying Xue,
Rong Chen, Pramod Nair, Zhi Guang Jia