Atomistic Simulations and Design in Biology

* Co-supervised with Peter Bond

** Co-supervised with Tan Meng How (GIS/NTU)

Chandra VERMA
Principal Investigator

NGUYEN Ngoc Minh, LAMA Dilraj, SRINIVASARAGHAVAN KannanResearch Scientists

Pietro ARONICA, Daniel A HOLDBROOK, Stephen J. FOX, Dilraj LAMA, NGUYEN Thanh Binh, Mohan R. PRADHAN, Yaw Sing TAN, Shila YADAHALLI, Akshita KUMAR (NTU), Jan MARZINEK Postdoctoral Scientists

Xiong An LEEResearch Associate

Megan B. COWAN, Mara KOZIC, Yasmina MHOUMADI, Lauren M. REID, Aishwary T. SHIVGAN*, Harini SRINIVASAN**, Dale STUCHFIELDPhD Students

Mechanisms underlying biology at a molecular level are explored through identifying and/or mapping the interactions of proteins with other proteins, nucleic acids, ligands. The methods/tools used are computational and combine representations at various levels, from the coarse grained to the fully atomistic. The work builds upon foundations that are rooted in rigorous computational biochemistry benchmarked extensively against available experimental data. Simulations complement extensive collaborations with experimental laboratories to provide incisive insights into biology at an atomic level. The group's current research focuses on the p53 pathway, kinases, translation initiation, antimicrobials and basic computational biophysical chemistry. The toolbox used consists of: construction of models based on "imagination with a whiff of hand-waving", homology modelling, molecular dynamics, energy landscapes, reaction paths, ligand-protein/protein-protein dockings including virtual screening. The group couples the molecular underpinnings of biomolecular regulation with ligand/drug discovery and protein/peptide design both from a therapeutic as well as a (bio)technological perspective.

Stapled Peptides: p53, eIF4E & Other Pathways

An extensive program with Sir David Lane combining computer modelling, biophysics, crystallography, molecular/cell biology, investigating the relationship between structural-functional aspects of the p53 family has revealed interesting nuances about the p53 pathway (BMC Biol 2017; Cell Death Diff 2017). These have guided us in designing a set of novel constrained (stapled/stitched) peptides whose ability to enter cells and specifically target the p53-MDM2 axis with nanomolar affinities, thusactivating p53, has opened a new avenue for designing therapeutics (highlighted in Nature Med 19; 120; 2013). A major effort currently underway is focused on understanding the mechanism of cellular permeabilization and nuclear entry of these peptides and subsequently in using these peptides as vehicles for delivering cargo into cells. A breakthrough has recently been achieved in the successful design of the first stapled non-helical peptides which suddenly opens new avenues for targeting and expanding the traditionally undruggable universe of proteinprotein interactions. This collaboration has brought in partners from the Universities of Edinburgh, Cambridge, Dundee, Southampton, Newcastle and Harvard and with the pharma Ipsen and MSD.

Staple Diets
^ Staple diets - A major program designing peptides as interrogative tools and potential therapeutics is ongoing. Combining molecular design guided by the associated molecular dynamics of peptides (left panel in figure, Sci Rep 2017b), we have designed several novel helical stapled peptides and non-helical stapled peptides (importin alpha 1, middle panel, Angew Chem Int Ed Engl. 2017 56:524 and Tankyrase 2, panel B in figure, JACS 2017)

In parallel, efforts are underway to understand the mechanisms of the translational initiation cascade and inhibit a key component in this pathway, eIF4E, which offers opportunities as a major target for therapeutic intervention in several cancers. Recent design efforts combined with extensive biophysical and structural analyses have led to the design of low nanomolar inhibitory stapled peptides. The recent developments and the excitement generated in the p53 field have been outlined in articles in Nature Reviews Drug Discovery, Nature Reviews in Cancer, Nature Reviews in Clinical Oncology that has been published by the joint efforts of teams from Singapore, Karolinska, Cambridge & Harvard Universities. The program is supported by generous funding from A*STAR and pharma.

Novel Antimicrobials

A highly successful interdisciplinary program with the group of Prof Beuerman at the Singapore Eye Research Institute and researchers at Nanyang Technological University, National University of Singapore, Singapore General Hospital and Duke-NUS has resulted in the design of novel antimicrobials (Front Neurosci 2017). These molecules target membranes with rapid killing times, are non-toxic to human cells and appear to avert resistance in bacteria. The greater anionicity of the bacterial membranes appears to be responsible for the rapid adsorption and hence killing of the former and for the non-toxicity of these cationic molecules; the inability of bacteria to easily remodel their membranes possibly leads to their susceptibility. The molecules work against a range of gram-positive and gram-negative organisms including resistant MRSA. A unique platform outlining the first reported in-membrane fragment based design method has been developed and several patents filed. The project has attracted generous funding from ETPL/A*STAR, NMRC. A spinoff company has been set up ( In a collaborative project with the Institute of Materials Research & Engineering (A*STAR) and SERI, we are combining simulations with experiments to demonstrate the mechanism of antimicrobial actions and selectivities of novel polymers.

The Kinase Pathways

In a large translational effort, the group is engaged with experimentalists (Dr Scaltriti, MSKCC) and clinicians (Prof Baselga, MSKCC) at Memorial Sloan Kettering and Dr Daniel Tan (GIS, SGH, NCC Singapore) studying the effects of small molecule and antibody based therapies for breast/lung cancers (Cancer Cell 2016). This work is now directed at the putative effects of mutations and SNPs (Sci Reps 2017a) in patients on clinical inhibitors.

Novel antimicrobials against resistant bacteria
^ Novel antimicrobials against resistant bacteria - Multiple molecules of the antibacterial peptide melittin (cyan) modelled interacting with a model vesicle (made up of POPC molecules)

In addition to the translational and clinical focus, the group is also engaged in exploring a variety of problems that underpin fundamental questions such as the role of water in modulating biomolecular function (Structure 2017; J Invest Dermatol 2017), developments of analytical processes, relationships between flexibility, thermodynamics, kinetics and function in biomolecules, methods to restabilize mutant proteins to wild type functionality and a major program with Prof Ali Miserez at NTU on biomaterials inspired by marine organisms (Bomacromolecules 2017).

Anticancer drug Afatinib (magenta sticks)
^ Anticancer drug Afatinib (magenta sticks) bound to mutant EGFR (19del; grey) mediates its unique effects through a single water molecule (red sphere). Several SNPs (L777Q, M766F, I759V, L788F, D855G, F856Y and G857E) are located near the water molecule and are shown coloured.

Finally, our expertise is integrated with that of several other labs in Singapore, in a multidisciplinary effort funded by the Ministry of Education, to combine the spatio-temporal dynamics of biomolecules across multiple scales into a seamless integrated mechanism that may yield insights into biology. The testbed for this effort is the Dengue virus which has major socio-economic impact in Singapore; several significant discoveries have already emerged such as the intimate role of glycosylation in antibody-virus interactions which is being explored for guiding antibody design strategies.

The virtual screening and peptide design efforts of the group are extended to collaborations with various groups within A*STAR (including the Experimental Therapeutics Centre, IMCB, IMB, SIGN, p53Lab, MEL, SBIC, ICES), the hospitals in Singapore, research centres (National Cancer Centre, Cancer Science Institute, LKC), universities (NUS, NTU, Duke-NUS) and organizations elsewhere (Univ of Cambridge, Karolinska Instt, Univ of Montreal), who carry out the synthesis and experimental investigations of the compounds (eg JACS 2017). Programs that combine the strengths of various institutes, hospitals and universities in Singapore towards peptide engineering, wound healing and precision medicine are generously funded by the Industry Alignment Fund Pre-Positioning grant. Combining a new yeast-based platform and modelling with colleagues in A*STAR at IMCB and BTI have resulted in a novel potential therapeutic for wet-AMD which is now being pursued in a new spinoff Sinopsee Therapeutics.

The success of the group in interfacing the nanoscale with experimental observations has encouraged several experimental groups worldwide to participate with us. These have also resulted in joint graduate programs with various universities including NCBS, IISc, Southampton, Manchester, Dundee, Edinburgh, Liverpool.

Model of antibody-virus interactions
^ Model of antibody-virus interactions: shown is the Dengue virus with the envelope proteins (red, blue, yellow) with 90 copies of the Fab domains of the 2D22 broadly- neutralising antibody (green). (joint effort with Peter Bond, BII)

Atomistic Simulations and Design in Biology Members

Dr. VERMA Chandra
Senior Principal Investigator
  Biography Details
Dr. VERMA Chandra Principal Investigator
Dr. NGUYEN Ngoc MinhResearch Scientist
Dr. KANNAN SrinivasaraghavanResearch Scientist
Dr. LAMA DilrajResearch Scientist
Dr. FOX Stephen JohnPostdoctoral Fellow
Dr. TAN Yaw SingPostdoctoral Fellow
Dr. KHARE Shruti VijayPostdoctoral Fellow
Dr. LI JianguoPostdoctoral Fellow - SERI
Dr. MALIK Ashar JamilPostdoctoral Fellow
Dr. YADAHALLI ShilpaPostdoctoral Fellow
Dr. THANH BINH NguyenPostdoctoral Fellow
Dr. PRADHAN Mohan Rajan Postdoctoral Fellow
Dr. KUMAR AkshitaPostdoctoral Fellow - NTU
Dr. ARONICA PietroPostdoctoral Fellow
Mr. CHEW Yi HongResearch Officer
Ms. SRINIVASAN Harini PhD student
Mr. SHIVGAN Aishwary Tukaram PhD student
Ms. MHOUMADI Yasmina PhD student
Ms. REID Lauren Marie PhD student
Ms. COWAN Megan Butler PhD student
Mr. Dale Stuchfield * PhD student
Dr. LIU Wei Collaborator

This section is still work in progress.