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