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 Chandra Verma
#07-38, level 7 Matrix (Biopolis)
Bioinformatics Institute, A*STAR
Email: chandra@bii.a-star.edu.sg
Tel: (65)-6478-8273
Research interests
structures
- dynamics - functions in proteins: in silico stories
Research
in our group utilizes atomistic computer models to probe and
provide mechanistic insights into fundamental processes in biology. We
utilize the usual suspects: construction
of models based on
"imagination with a whiff of hand-waving", homology modelling,
molecular dynamics, free energy, normal modes, reaction paths to
examine shape shiftings in proteins, electrostatics,
ligand-protein/protein-protein dockings; the
docking program also includes the development of novel or modifications
of existing scoring methods.
On the one hand we examine how
native and
mutant forms of proteins may (mis)function while on the other we have
an extensive program that is directed towards ligand/drug discovery and
protein/peptide design both from a therapeutic as well as a
(bio)tehcnological perspective.
We are also
involved in an extensive program of training/education for students of
all levels in Singapore
(school, poly, univ)
Phd Programs: An extensive program is available on a range of projects
to carry out joint PhDs with
Imperial College; Dundee University; Cambridge University; Karolinska
Institute
Please note
that our internship programs are only
open to students who are currently
enrolled in Singapore
and our PhD programs are open
only to Singaporean citizens.
Current
projects in the laboratory
include:
Tales along the
p53
pathway: Ever felt
stressed! Not the usual
stress of having to decide which side of the bed to wake up
from....This is about the stress
of events such as serious exposure to the sun followed by a blushing
redness and associated dismal peeling off of the skin. It is this
peeling off which is brought about by the magic guardian angel of the
cell, the protein p53. It is due to this p53 that mutant cells are
being discarded into oblivion in the form of peels...How and why
exactly (or well close enough for practicality) this happens is
reasonably mysterious and is the
subject of an intense research effort here. Together in close
association
with the experimental group of Prof David Lane (separated by a mere 50
metres) we are probing various aspects of structure, dynamics, function
and design of components of this elusive system. Projects include
investigations of the effects of phosphorylations along this
pathway; the energetics of the interactions of p53 with its various
partners; the assembly of various components of the p53
machinery (if you are bored already then amuse yourself with dna binding
domains of p53 dancing along the DNA or the
flapping tetramerization domain of p53);
design of peptidomimetics to disrupt
various interactions along the p53 pathway.
current
collaborators: Prof Sir David Lane (IMCB,
Singapore); Prof Malcolm Walkinshaw (Univ
of Edinburgh); Sabhapathi Kannagah (NCC,
Singapore).
Cell cycle
modulation by Cyclins: Cyclins
and Cyclin dependant kinases are the dynamic duo of cell cycle
regulation. They form a large family and in various combinations,
regulate cell cycle progression by phosphorylating key proteins. The
structural and energetic basis of how the different partners
orchestrate this by specifically interacting with substrate proteins is
a subject that we (together with 1000s of others) are investigating
with our expeirmental partners. One of our contributions is
hypothesizing that electrostatic factors play a major role in their
specificities. The figure shows that the key differnce between Cyclin A
and cyclin B in differing substrate specificities seems to stem from
contrasting surface characteristics of the two proteins: anionic Cyclin
A ready to accomodate the cationic ZRXL motif of subsrtates and a
cationic cylcin
B rather reluctant towards the ZRXL: cyclin-electrostatic-discrimination
current
collaborators: Prof Sir David Lane (IMCB,
Singapore)
The
defensins: The
defensins form part of our innate immunity. They are small cationic
amphipathic proteins, bridged by 3 disulphide bridges that confers upon
them a rigid scaffolding. So what makes them so versatile and
irritatingly enigmatic? We have a major collaborative venture where we
use computational methods to design new variants of defensins that are
then synthesised and probed for activity (mass
spec, hplc, nmr, bacteriology, virology, fungology - yes i know this is
wrong but i do not remember the correct word just now). This feeds back
into our design strategies which are also augmented with fundamental
studies of what it is that underpins their behaviour. For
example we find that while hydrophobc forces are responsible for the
oligomers to stay together despite each monomer cationically repelling
the other, they do display a large increase in overall cationicity upon
oligomerization...well lets start with dimerization anyway!! This
may increase their concentration at the anioinic bacterial cell wall. We have formed
a multi-disciplinary team,
SCAMP (Singapore Consortium for Antimicrobial Peptides) to direct a
collective effort against
infectious
diseases in Asia, such as fungal infections of the eye. This
team, funded in
part by the National Medical Research Council of Singapore,
includes chemists (Drs. Zhou Lei and Shouping Liu) cell and molecular
biologists (Drs. Beuerman and Li), microbiologists (Drs. Yap and Poh)
and
our own little bioinformatics expertise who have
put together a wonderful database
where one can
trawl at
leisure.
current
collaborators: Prof Roger Beuerman (SERI, Singapore); NUS, DSO.
Protein Kinase-C: The
Protein Kinase C superfamily contains
10 known
isoforms, involved in varied cellular signalling pathways. We are
investigating (or at least did when the universe seemd to hev begun!!)
a much neglected region called the V5 domain, located at the
C-terminus of the protein, which is believed to be necessary for the
unique activity of each isoform. Together with an experimental group,
we (mainly our protein sculptor
Derek) use computational methods to probe the
conformation
and dynamics of the V5 domain and provide a mechanistic basis for
experimentally derived
results of truncation mutants. Currently our findings indicate an
intricate mechanism of control that is exerted differentially
across the isoforms and is modulated by key hydrogen bonds that link
the two domains and a helix of the kinase This is being coupled to the
development
of
novel therapeutic agents that target PKCs.
current
collaborators: Dr Duan
Wei (Dept of Biochemistry, NUS)
Ligand screening: We
are setting up a ligand screening
facility here in Singapore. In its most
elemental form, the service will provide, upon given a 3-dimensional
structure of a protein, a black box wherein a bucketload of small
molecules will be thrown at the protein and the ones that attach
themselves to the protein with
reasonable stickiness will be handed back to the researcher. Once we
become more ambitious and generous, the facility will also enable the
"contsruction" of a 3-dimensional structure of a protein whose sequence
is "fed" in. The facility
will evolve into a program that will encompass and be integrated with
some bioinformatics tools to generalize the findings.
Other
random meanderings
This
story has been quite beneficial to all involved on the one hand and on
the other extreme where ignorance still reigns, does at least provide
beautiful animations. Most of the work is carried out with the "wets"
although certain projects do involve occasional meanderings in pure
theoretical space. Click here for some picturesque
landscapes
Group publications
(Group
publications)
(pre-Singapore
publications)
Current
hard(ly)-working babies in the BMAD family:
Ex
hard(ly)-working babies in the BMAD family:
Anita S
Bryan
L Daniel L
Derek S Huijun L
Madhu A Shalin S
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