Multiscale Simulation, Modelling and Design

BII - Multiscale Simulations and Design in Biology


We build computational models that contribute to our understanding of mechanisms of disease and host immune responses, with a particular focus on infective pathogens. Our main method of choice is molecular simulation, using multiscale approaches that allow us to access a broad range of spatio-temporal scales, from atomically-detailed systems to highly simplified coarse-grained resolutions. We interact closely with our numerous experimental collaborators, and develop new ways to integrate diverse structural, biophysical, and biochemical data into models that elucidate biomolecular dynamics and function, and ultimately enable us to work towards novel therapeutic strategies.

Enveloped Virus-Host Interactions

Enveloped viruses infect millions of people worldwide each year, exacerbated by ongoing climate changes and globalization. Traditionally, we have focused on the mosquito-borne RNA flavivirus, dengue virus, which represents a significant burden to human health and the economy in Singapore. As part of a Singapore-wide collaborative team of researchers spanning NUS, A*STAR, Duke-NUS, and SGH, we recently elucidated how such viruses can “sense” their local environments in order to modulate their dynamics and propagate the viral life cycle, and we hypothesize that this may expose vulnerable hotspots on the virus for targeting by antibodies or antiviral drugs.


Figure 1: Multiscale modeling in combination with experimentally derived structural data were used to study an antibody (cyan) in complex with dengue virus envelope proteins (blue, red, orange). On the left, the entire viral complex is shown; on the right, simulations reveal the dynamic nature of antibody-epitope interactions.

SARS‑CoV‑2: Allostery, sugars, and a bacterial boost

We are also leveraging the methods we have developed for flaviviruses to other enveloped viruses [6] such as coronaviruses including SARS‑CoV‑2 prompted by the ongoing COVID-19 pandemic. In particular, we have extensively characterized the structure and dynamics of the SARSCoV- 2 spike protein which covers the pathogen’s surface and is crucial for infection. We have uncovered significant evidence for the importance of allostery in its function. Thus, a recent intra-BII joint effort with the Berezovsky group has provided a detailed map of allosteric signaling on the spike protein, providing a means to predict potential mutational sites that may lead to emerging variants and also facilitate new allosteric drug discovery [7]. Similarly, a multidisciplinary study with NUS and Penn State University revealed that binding of the spike protein to its human cell surface receptor allosterically triggers distinct structural changes at hotspots that may govern downstream processes critical to viral entry and antibody recognition [8].

The complexity of SARS‑CoV‑2 pathogenesis and therapy are highlighted by two ongoing research directions, linked to our characterization of the interactions of the spike protein with non-viral factors. On the one hand, we have shown with researchers at Lund University that the spike protein can bind bacterial lipid molecules which are inflammatory in humans, which may lead to more serious disease in susceptible patients, such as those with metabolic syndrome [9]; this opens up potential new therapeutic and diagnostic avenues, as well as highlighting an interesting link between viral infection and the microbiome. On the other hand, building on our previous multiscale glycan modelling efforts [10], we have been computationally mapping the dynamics of the glycan coating of the spike protein as part of a global collaboration [11-12]. Predicting how the spike protein influences local glycan structure has helped to reveal why constructs derived from different labs are highly similar and closely resemble their viral counterpart, rationalizing the current success of spike-based vaccines targeting SARSCoV- 2 (Figure 2). Supported by an ID HTPO SF grant, we are expanding this work to support the surveillance of emerging variants of concern to assess possible effects of mutations upon function or vaccine escape.


Figure 2. Molecular dynamics simulations of full-length glycosylated spike protein (grey) from SARS‑CoV‑2 validated by mass spectrometry data revealed different accessibility of each glycosylation site to glycan processing enzymes (cyan) that determine the final state of glycosylation.


Antimicrobial resistance is now a leading cause of death worldwide, and there is an urgent need to discover new ways to treat bacterial infections. This is a particular issue for Gram-negative bacteria, for which no novel class of antibiotic has reached the market in over 50 years. We recently helped to resolve the mode of action of such an antibiotic. In collaboration with the University of Basel, the natural cyclic beta-peptide darobactin was shown to bind to the essential insertase BamA, thereby blocking the folding and insertion of outer membrane proteins (Figure 3); the unusual nature of its binding mode was found to make it particularly robust to resistance [13]. We have similarly been working with researchers at NUS on synthetic cyclic beta-hairpin peptides, in which small mutational variations can impart a wide range of antimicrobial activities via bacterial membrane disruption [14]. Finally, a complicating factor in overwhelming infections is sepsis, during which components of the immune system become overstimulated by inflammatory bacterial toxins leading to wholebody inflammation and potentially death. By integrating diverse structural, biophysical, and cellular data in collaboration with Lund University, we have determined previously undisclosed anti-inflammatory mechanisms of endogenous peptides found in wounds during blood clotting [15-16], which are being leveraged to develop new ways to treat infections.


Figure 3. The novel mode of action of antibiotic darobactin revealed by experiment and simulation. The cyclic peptide mimics a beta-strand and forms rigid backbone-backbone hydrogen-bonding interactions with the substrate recognition site of BamA in the Gram-negative bacterial outer membrane.


 Senior Principal Investigator  BOND Peter J.   |    [View Bio]   
 Senior Post-Doctoral Research Fellow  KRAH Alexander 
 Senior Post-Doctoral Research Fellow MARZINEK Jan
 Post-Doctoral Research Fellow SAMSUDIN Mohd Firdaus 
 Post-Doctoral Research Fellow PALUR Venkata Raghuvamsi 
 PhD Students WALLER Callum Peter 
 PhD Students DAVIES Thomas Stefan 
 PhD Students TUPINA Dagnija 

Selected Publications