Multiscale Simulation, Modelling and Design

Bii Research Msmd

Multiscale Modelling

We use multiscale molecular modelling and simulation, spanning atomically detailed systems to highly simplified coarse-grained models, to understand molecular mechanisms underlying disease and translate these insights into therapeutic discovery and design. A key strength of our work is building biologically realistic molecular models of complex systems, ranging from glycosylated membrane proteins and therapeutic assemblies to viral envelopes and whole-virus particles, and using these models to identify new opportunities for therapeutic intervention. We integrate molecular simulation with structural modelling, free-energy methods and AI-assisted approaches, including strategies to uncover cryptic drug-binding pockets. Working closely with experimental collaborators, we combine structural, biophysical, biochemical and cellular data to link molecular mechanism with therapeutic discovery. Our research has a particular focus on infectious diseases and virus modelling, alongside programmes in membrane receptor drug discovery and antibody therapeutics.

Bii Research Msmd Figure

Infectious Disease & Anti-Infective Therapeutics

We have a major focus on multiscale modelling of viruses and other infectious pathogens, ranging from individual viral proteins and membrane-fusion mechanisms to realistic models of viral envelopes and whole-virus particles. These models allow us to investigate viral dynamics, glycosylation, antibody recognition, membrane fusion and other molecular processes underlying infection. We increasingly translate this mechanistic understanding towards therapeutic discovery, including cryptic-pocket identification and druggability analysis, broad-spectrum antiviral design, vaccines and virus-like particles. Our work on flaviviruses and coronaviruses has established computational approaches for identifying previously hidden, potentially druggable pockets in dynamic viral proteins, providing new opportunities for structure-guided antiviral discovery. Our anti-infective research extends to bacterial pathogens and antimicrobial resistance, where multiscale simulations provide molecular insight into bacterial membranes, antimicrobial mechanisms and potential therapeutic targets. We also collaborate extensively with P&G on antiviral and antibacterial molecule discovery, combining computational and experimental approaches to understand how candidate molecules interact with and disrupt pathogen structures and membranes. Membrane Receptors & Drug Discovery We investigate the structure, dynamics and activation mechanisms of therapeutically important membrane receptors and translate these insights into structure-guided drug discovery. Drawing on our expertise in membrane proteins and dynamic-pocket identification, we integrate multiscale molecular simulations with structural biology, virtual screening, free-energy calculations, AI-assisted approaches and collaborative experimental validation. Our work spans GPCRs, receptors in the innate and adaptive arms of the immune system, and other therapeutically important membrane proteins, from fundamental studies of receptor activation and ligand recognition to therapeutic discovery. Current programmes include agonist discovery for therapeutically relevant GPCRs and targeting the placental Fc receptor to prevent maternally derived diseases in the foetus, demonstrating how mechanistic molecular modelling can be integrated with screening, experimental validation and compound optimisation to support therapeutic discovery. Antibody Therapeutics We develop integrative multiscale models of antibodies and their targets to understand molecular recognition, specificity and therapeutic mechanisms. Our work spans different antibody isotypes and applications in cancer and infectious disease, from antiviral antibodies to antibody-drug conjugates. By combining structural information with molecular simulations, we investigate how antibody structure, dynamics, glycosylation and target interactions determine therapeutic behaviour. Collaborative programmes with EDDC apply these approaches to characterise antibody-receptor interactions, determinants of binding and specificity, and mechanisms of action, enabling rational optimisation of cancer therapeutics.

Research Support

Our recent research is supported by competitive national research programmes, strategic initiatives and industry partnerships, including:

  • NMRC Open Fund Individual Research Grant (OF-IRG): placental FcRn inhibition.
  • NRF Competitive Research Programme (CRP): dengue RNA vaccine development.
  • PREPARE: pan-coronavirus fusion inhibitors.
  • NRF Singapore Academies Southeast Asia Fellowship (SASEAF): coronavirus dynamics, host-virus interactions and therapeutics.
  • National Initiative for RNA Biology and its Applications (NIRBA): RNA delivery and endosomal escape.
  • A*STAR-P&G IAF-ICP: surfactant-bacterial membrane interactions.
 Senior Principal Investigator   BOND Peter J.   |    [View Bio]   
 Senior Scientist  MARZINEK Jan
 Senior Scientist  SAMSUDIN Mohd Firdaus 
 Scientist  PALUR Venkata Raghuvamsi 
 Scientist  SOMBOON Kamolrat
 Scientist  MASIREVIC Srdan
 PhD Students  HAREED Ayub Mohamed

  1. Samsudin F, Zuzic L, Marzinek JK, Bond PJ. (2024). Mechanisms of allostery at the viral surface through the eyes of molecular simulation. Curr Opin Struct Biol. 84:102761.  

  2. Zuzic L, Marzinek JK, Anand GS, Warwicker J, Bond PJ. (2023). A pH-dependent cluster of charges in a conserved cryptic pocket on flaviviral envelopes. Elife. 12:e82447.

  3. Chawla H, Jossi SE, Faustini SE, Samsudin F, Allen JD, Watanabe Y, Newby ML, Marcial-Juárez E, Lamerton RE, McLellan JS, Bond PJ, Richter AG, Cunningham AF, Crispin M. (2022). Glycosylation and Serological Reactivity of an Expression-enhanced SARS-CoV-2 Viral Spike Mimetic. J Mol Biol. 434:167332.

  4. Petrlova J, Samsudin F, Bond PJ, Schmidtchen A. (2022). SARS-CoV-2 spike protein aggregation is triggered by bacterial lipopolysaccharide. FEBS Lett. 596:2566-2575.

  5. Samsudin F, Raghuvamsi P, Petruk G, Puthia M, Petrlova J, MacAry P, Anand GS, Bond PJ*, Schmidtchen A*. (2023) SARS-CoV-2 spike protein as a bacterial lipopolysaccharide delivery system in an overzealous inflammatory cascade. J Mol Cell Biol. 14:mjac058. (Journal Cover Article).

  6. Tan ZW, Tee WV, Samsudin F, Guarnera E, Bond PJ, Berezovsky IN. (2022). Allosteric perspective on the mutability and druggability of the SARS-CoV-2 Spike protein. Structure. 30:590-607.e4.

  7. Tulsian NK, Raghuvamsi PV, Qian X, Yue G, Shunmuganathan BD, Samsudin F, Hwa WY, Jianqing L, Purushotorman K, Kozma MM, Wang B, Lescar J, Wang CI, Gupta RK, Bond PJ*, MacAry PA*. (2023). Defining neutralization and allostery by antibodies against COVID-19 variants. Nature Commun. 14:6967.

  8. Zuzic L, Samsudin F, Shivgan AT, Raghuvamsi PV, Marzinek JK, Boags A, Pedebos C, Tulsian NK, Warwicker J, MacAry P, Crispin M, Khalid S, Anand GS, Bond PJ. (2022). Uncovering cryptic pockets in the SARS-CoV-2 spike glycoprotein. Structure. 30:1062-1074.e4.

  9. Mah MG, Linster M, Low DHW, Yan Z, Jayakumar J, Samsudin F, Wong FY, Bond PJ, Mendenhall IH, Su YCF, Smith GJD. (2023). Spike-independent infection of human coronavirus 229E in bat cells. Microbiol. Spectr. 11:e0348322.

  10. Waller C, Marzinek JK, McBurnie E, Bond PJ*, Williamson PTF*, Khalid S*. (2023). Impact on S. aureus and E. coli membranes of treatment with chlorhexidine and alcohol solutions: insights from molecular simulations and nuclear magnetic resonance. J Mol Biol. 435:167953.

  11. Khalid S, Schroeder C, Bond PJ, Duncan AL. (2022). What have molecular simulations contributed to understanding of Gram-negative bacterial cell envelopes? Microbiology. 168:001165.

  12. Guilvout I, Samsudin F, Huber H, Bond PJ, Bardiaux B, Francetic O. (2024). Membrane platform protein PulF of the Klebsiella type II secretion system forms a trimeric ion channel essential for endopilus assembly and protein secretion. mBio. 15:e0142323.

  13. Tupiņa D, Krah A, Marzinek JK, Zuzic L, Moverley AA, Constantinidou C, Bond PJ. (2022). Bridging the N-terminal and middle domains in FliG of the flagellar rotor. Curr Res Struct Biol. 4:59-67.

  14. Krah A, Vogelaar T, de Jong SI, Claridge JK, Bond PJ, McMillan DGG. (2023). ATP binding by an F1Fo ATP synthase ε subunit is pH dependent, suggesting a diversity of ε subunit functional regulation in bacteria. Front Mol Biosci. 10:1059673.

  15. Puthia M, Marzinek JK, Petruk G, Ertürk Bergdahl G, Bond PJ, Petrlova J. (2022). Antibacterial and Anti-Inflammatory Effects of Apolipoprotein E. Biomedicines. 10:1430.

  16. Ragunathan P, Sae-Lao P, Hamela C, Alcaraz M, Krah A, Poh WH, Ern Pee CJ, Hou Lim AY, Rice SA, Pethe K, Bond PJ, Dick T, Kremer L, Bates RW, Grüber G. (2024). High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo. J Biol Chem. 300:105618.

  17. Krah A, Ragunathan P, Bond PJ, Grüber G. (2024). Variations of the Mycobacterium abscessus F-ATP synthase subunit a-c interface alter binding and potency of the anti-TB drug bedaquiline. Biochem Biophys Res Commun. 690:149249.

  18. Krah A, Grüber G, Bond PJ. (2022). Binding properties of the anti-TB drugs bedaquiline and TBAJ-876 to a mycobacterial F-ATP synthase. Curr Res Struct Biol. 4:278-284.

  19. Petruk G, Puthia M, Samsudin F, Petrlova J, Olm F, Mittendorfer M, Hyllén S, Edström D, Strömdahl AC, Diehl C, Ekström S, Walse B, Kjellström S, Bond PJ, Lindstedt S, Schmidtchen A. (2023). Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs. Nature Commun. 14:6097.

  20. Puthia M, Petrlova J, Petruk G, Butrym M, Samsudin F, Andersson MA, Strömdahl AC, Wasserstrom S, Hartman E, Kjellström S, Caselli L, Klementieva O, Bond PJ, Malmsten M, Raina DB, Schmidtchen A. (2023). Bioactive suture with added innate defense functionality for the reduction of bacterial infection and inflammation. Adv Healthc Mater. e2300987. (Journal Cover Article).

  21. Kolloff C, Mazur A, Marzinek JK, Bond PJ, Olsson S, Hiller S. (2022). Motional clustering in supra-τc conformational exchange influences NOE cross-relaxation rate. J Magn Reson. 338:107196.

  22. Dutta C, Krishnamurthy P, Su D, Yoo SH, Collie GW, Pasco M, Marzinek JK, Bond PJ, Verma C, Grélard A, Loquet A, Li J, Luo M, Barboiu M, Guichard G, Kini RM, Kumar PP. (2023). Nature-inspired synthetic oligourea foldamer channels allow water transport with high salt rejection. Chem. 9:2237-2254.

  23. Koh J, Itahana Y, Krah A, Mostafa H, Ong MM, Iwamura S, Vincent DM, Krishnan SR, Ye W, PWC Yim, Khopade TM, Chen K, Kong PS, Wang LF, Bates RW, Kimura Y, Viswanathan R*, Bond PJ*, Koji Itahana*. (2024). From Bats to Drugs: Exploring Cyclic Tryptophan Diketopiperazine as ABCB1 Inhibitors. Commun Chem. In press.

  24. Li E, Yaochai MY, Ng JM, Huber RG, Bond PJ, Krah A. (2023). Observation of multiple protein temperature transitions dependent upon the chemical environment. J Mol Liq. 385:122348.

  25. Shivgan AT, Marzinek JK, Krah A, Matsudaira P, Verma CS, Bond PJ. (2024). Coarse-Grained Model of Glycosaminoglycans for Biomolecular Simulations. J Chem Theory Comput. 20:3308-3321. (Journal Cover Article).