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 physical principles and 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 molecular underpinnings of biomolecular regulation with ligand/drug discovery and protein/peptide design are translated into (bio)technological, therapeutic and clinical settings. The toolbox used consists of: construction of models based on “imagination with a whiff of hand-waving”, homology modelling, molecular dynamics, free energy landscapes, reaction paths, ligand-protein/proteinprotein dockings including virtual screening, molecular design, machine learning/AI.


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 has revealed interesting nuances about the p53 pathway. These have guided us in designing a set of novel constrained (stapled/stitched) peptides (Figure 1) 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 (Nature Med 2013 19:120). A major effort with pharma companies 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 (J Chem Phys 2022 156:065101; Chem Sci 2022 13:1957; J Coll Interf Sci 2021 604:670). This is being extended to developing constrained/ peptides against other targets such as KRAS (Chem Sci 2021 12:15975), eIF4E to inhibit translation initiation for a range of cancers (BBA Gen 2021 1865:129775). A novel D-amino acid containing stitched peptide has been designed and validated to activate p53 and has recently been patented jointly with a pharma. This collaboration has brought in partners from local organizations, international universities, and pharma industry. The 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, 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 late 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 bacterial membranes rapidly, are non-toxic to human cells and appear to avert resistance in bacteria (JCIM 2021 61 3172; Front Pharmacol 2021 2793). 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 with biotech are in progress.


The Kinase Pathways

In a large translational effort, the group is engaged with experimentalists (Dr Scaltriti, MSKCC; Dr Cocco, Univ Miami Health System), Dr Uttam Surana (IMCB) and clinicians Dr Daniel Tan (NUHS), 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 (Nat Commun 2020) in patients on drugs used in the clinic. 

Modelling combined with biochemical assays show how patients that develop resistance mutations in kinases to type I inhibitors benefit from type II inhibitors demonstrating that adaptive conformational resistance can be abrogated by shifting kinase engagement modes. Cancer Discovery 2021
As part of the National Precision Medicine program (PRECISE), in a large island wide effort, this project of national significance is dedicated to developing and mining platform for predicting the effects of missense variations in proteins and their effects on drugs as an aid to assist clinicians. In parallel, a new program that harnesses the power of quantum computers is being funded by NUS Quantum Engineering Program to identify critical problems in manipulating biomolecules and predict variant effects using quantum machine learning algorithms on near-term quantum computers.
Left: Protein with ligand/drug in dark blue bound;
Right: Protein with SNP (green spheres) with ligand/drug bound; The effects of the SNP on the binding of ligand/drug are estimated


 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
 Senior 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 RICHMOND John, ARAP (Univ Manchester)

Selected Publications