Multiscale Simulation, Modelling and Design

BII - Multiscale Simulations and Design in Biology


We build computational models that primarily contribute to our understanding of mechanisms of infectious disease and the resultant host immune response. 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. We focus on the mosquito-borne RNA flavivirus, dengue virus, which represents a significant burden to human health and the economy in Singapore. We are also now leveraging the methods we have developed for flaviviruses to understand coronaviruses, another group of enveloped RNA viruses which include SARS‑CoV‑2, the causative agent of the COVID-19 pandemic.

We are supported by an NRF-funded CRP grant which seeks to understand the mechanisms by which flaviviruses infect cells and interact with host immune factors, towards rational vaccine development. As part of a Singapore-wide collaborative team of researchers spanning NUS, A*STAR, Duke-NUS, and SGH, we have discovered that flaviviruses "sense" the different local microenvironments associated with the host to modulate their dynamics and propagate the viral life cycle, and we hypothesise that this may expose vulnerable hotspots on the virus for targeting by antibodies or antiviral drugs.

Our previously developed "virtual flavivirus" models are being leveraged to elucidate key molecular events associated with infection and antibody recognition (Figure 1). For example, a collaboration with Duke-NUS has led to the discovery that dengue may be able to "outsmart" vaccines by mutating when the patient has fever. We have shown how dengue virus particles can switch from a "smooth" to "bumpy" shaped morphology when transmitted from mosquito to human, corresponding to a change in physiological temperature from 29 to 37-40 degrees Celsius, and that this switch is reversible only in the presence of salt containing divalent cations such as magnesium or calcium. At normal body temperature, lab-adapted viruses can more easily adopt a "bumpy" shape than clinical strains isolated from patients, due to mutations in proteins on the surface of the virus. On the other hand, at a higher temperature mimicking a fever, all the strains change to a "bumpy" shape. Based on our models, we can show which mutations would lead to what shape of virus, which is important for developing tailored approaches for treatment of dengue infections, depending upon the viral strain and whether a patient is already suffering from dengue-induced fever.

Our models have also been applied to understand dengue virus maturation, and its dependence upon antibody interactions (Figure 1). Simulations of the entire immature dengue particle were used to explore the transition between intermediates identified by cryo-electron microscopy, revealing how antibodies may dislodge a protein fragment on the surface of the virus to expose a key fusogenic peptide necessary for fusion with host endosomal compartments enabling cellular infection. This provides a molecular rationale for the phenomenon of antibody dependent enhancement (ADE), which can lead to severe cases of dengue disease. In parallel, we are helping to elucidate the architecture of the viral core which encapsulates capsid proteins complexed with the genomic material of the virus, and exploring the potential of novel synthetic peptidomimetic compounds to inhibit viral infection.

BII - Multiscale Simulation, Modelling and Design Figure 1

Figure 1: Multiscale modeling in combination with experimentally derived structural data have revealed the mechanism by which dengue "senses" its environment to trigger progression along the viral life cycle, including "breathing" dynamics which may help it to evade immune recognition (top), and maturation assisted by host antibodies (bottom).

Host Defense and Immune Signaling

The mammalian innate immune system provides a crucial first-line response to infection, but its dysfunction can lead to a diverse range of inflammatory diseases. The Toll-like receptor 4 (TLR4) pathway is specialized for recognition of key molecular "patterns" in molecules derived from pathogens. Conversely, its over-stimulation during overwhelming infections can cause sepsis, a leading cause of mortality in Singapore and around the world, which is exacerbated by the growing crisis of antimicrobial drug resistance. With labs at the University of Cambridge, we have established the detailed mechanisms by which stimulatory molecules at the cell surface of Gram-negative bacteria, in particular lipopolysaccharide (LPS), are recognized by TLR4 in combination with its co-receptors CD14 and MD-2, as part of a "thermodynamic funnel" (Figure 2). Furthermore, we are working with researchers at the Baker IDI Heart and Diabetes Institute to understand the links between TLR4 and metabolic disease, and in collaboration with Duke-NUS, we are also unravelling the mechanisms by which interaction of secreted dengue lipoprotein particles with TLR4 may increase disease severity and lead to epidemics. Finally, by integrating diverse structural, biophysical, and cellular data in collaboration with researchers at LKCMedicine NTU and Lund University, we have determined previously undisclosed modes of interaction of components of the TLR4 pathway with endogenous thrombin-derived C-terminal peptides (TCPs) found in wounds during blood clotting. Such TCPs appear to have multi-functional antiseptic and antimicrobial activities, including a newly discovered capacity to bind to and competitively inhibit the CD14 co-receptor, thereby dampening inflammation (Figure 2); this may be leveraged in future to develop new ways to treat infections.

BII - Multiscale Simulation, Modelling and Design Figure 2
Figure 2: Multiscale simulations integrating biochemical and biophysical data has led to a unifying model for TLR4 pathway activation by bacterial LPS, and its inhibition by endogenous thrombin-derived C-terminal peptides (TCPs).


 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 

Selected Publications