Atomistic Simulations and Design in Biology

BII - Atomistic Simulations and Design in Biology


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 several bimolecular mechanisms including those associated with 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, molecular design, machine learning/AI. 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 the p53 laboratory of Prof Sir David Lane combining computer modeling, biophysics, crystallography, molecular/cell biology, investigating the relationship between structural-functional aspects of the p53 family (JMCB 2019) has revealed interesting nuances about the p53 pathway. 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, thus activating p53, has opened a new avenue for designing therapeutics (highlighted in Nature Med 2013 19:120). A major effort has been ongoing with MSD focused on understanding the mechanism of cellular permeabilization and nuclear entry of these peptides and subsequently in using these peptides as probes, therapeutics or vehicles for delivering cargo into cells (Chem Comm 2019; Chem Sci. 2019 10:6457; Molecules 2019). This is being extended to developing constrained/peptides against eIF4E to inhibit translation initiation for a range of cancers (Chem Sci 2019 1:2489). A novel d-amino acid containing stitched peptide has been designed and validated to activate p53, and has recently been patented jointly with MSD. The technology is being expanded to explore a variety of protein-protein interactions in cells for indications ranging from oncology to inflammation (Sci Rep. 2019 9:4913). This collaboration has brought in partners from local organizations, the Universities of Edinburgh, Cambridge, Dundee, Southampton, Newcastle and Harvard and with the pharma Ipsen and MSD.

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 MSD.

BII - Atomistic Simulations and Design in Biology Figure 1
Stapled diets –  A major program designing peptides disrupting proten-protein interactions as interrogative tools and potential therapeutics is ongoing. Combining molecular design with experiments we have been designing nanomolar stapled inhibitors of a variety of protein-protein interactions; left panel: a novel d-amino acid containing stitched peptide inhibitor of MDM2, bioarchive; middle panel: bis-triazole stapling a β-hairpin targeting the CK2α/CK2β interaction, Chem Sci. 2019 10 5056; right panel: covalent inhibitors of MDM2 using electrophile carrying stapled peptides, Chem Commun (Camb). 2019 55 7914.

Novel Antimicrobials

A highly successful interdisciplinary program with the group of Prof Beuerman at the Singapore Eye Research Institute and researchers at National University of Singapore, Singapore General Hospital, Duke-NUS and Tan Tok Sing Hospital has resulted in the design of novel antimicrobials. 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 (J Phys Chem B 2018 122 8698). 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. A spinoff company has been set up ( Recently we have developed a novel molecule that is able to disrupt the new mcr-1 resistant bacterial membrane (which is resistant to colistin) and enables colistin to be active at low doses. A patent has been filed and discussions for a new spinoff are in progress.

BII - Atomistic Simulations and Design in Biology Figure 2
As the last resort antibiotic, colistin is active against various Gram negative bacteria by disrupting the outer membrane. In the recent emergence of the mcr-1 bacteria, the outer membrane is decorated by an electrostatic net arising from an extensive hydrogen bond network between phosphate and amine groups, which non-covalently cross links the lipid A together, resulting in resistance to colistin (left panel shows normal bacterial membrane disrupted by colistin (in spheres) while on the right is a model of the mcr-1 bacterial membrane which is resistant to colistin (in spheres). .

The Kinase Pathways

In a large translational effort, the group is engaged with experimentalists (Dr Scaltriti, MSKCC), Dr Uttam Surana (IMCB) and clinicians Dr Daniel Tan (GIS, SGH, NCC Singapore), Dr Goh Boon Cher (NUHS) studying the effects of small molecule and antibody based therapies for cancers (Cancer Cell 2016). This work is now directed at the putative effects of mutations and SNPs (JCIM 2019a,c) in patients on drugs used in the clinic.

BII - Atomistic Simulations and Design in Biology Figure 3
Models of the mechanism of binding of the anticancer drug afatinib (magenta) bound to EGFR suggest that patients with SNPs (the annotations on the figure) can have significant effects on the binding of afatinib (the surface colours from blue to red represent binding energies of afatinib ranging from -4 to +4 kcal/mol); JCIM 2019c. The effects of a buried water (red sphere) using inhouse developed methods (NAR 2019) are also significant.

The translational and clinical focus of the group is backed by rigorous investigations into fundamental questions regarding the modulation of biomolecular function, developments of analytical processes, relationships between flexibility, thermodynamics, kinetics and function in biomolecules, role of water molecules and development of methods to enable discovery (Nat Commun 2019; NAR 2019; JICM 2019a,b,c,d; DDT 2019; NAR 2019 47(W1):W482)

The virtual screening and peptide design efforts of the group are extended to collaborations with various groups within A*STAR (including the Experimental Drug Discovery 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, MSKCC, Pasteur Institute), who carry out the synthesis and experimental investigations of the compounds. Programs that combine the strengths of various institutes, hospitals and universities in Singapore towards peptide engineering (Molecules 2019), wound healing, precision medicine (Cell 2019), bioimaging and small molecule discovery 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 has resulted in several new molecules against targets in oncology. A novel potential therapeutic for wet-AMD which is being pursued in our spinoff Sinopsee Therapeutics has shown exciting results in mice and is currently at the stage of seeking Series A funds. The computational expertise of the group is now being amalgamated in a new spinoff Aplomex which will be focused on designing peptides, proteins and antibodies.

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 Southampton, Manchester, Essex.


 Deputy Director (Research), Senior Principal Investigator  VERMA Chandra S.   |    [View Bio]   
 Senior Research Scientist  NGUYEN Ngoc Minh 
 Senior Research Scientist SRINIVASARAGHAVAN Kannan 
 Senior Research Scientist LI Jianguo
 Senior Post-Doctoral Research Fellow ARONICA Pietro
 Senior Post-Doctoral Research Fellow MALIK Ashar
 Senior Post-Doctoral Research Fellow KUMAR Akshita
 Post-Doctoral Research Fellow KHARE Shruti Vijay
 Post-Doctoral Research Fellow SHIVGAN Aishwary
 PhD Student COWAN Megan, ARAP (Univ Essex)
 PhD Student STAMATIS Dimitrios, ARAP (Univ Southampton)
 PhD Student NICOLAOU Sonia, ARAP (Univ Manchester)
 PhD Student STUCHFIELD Dale, ARAP (Univ Manchester)
 PhD Student MHOUMADI Yasmina, SINGA

Selected Publications