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.
Flaviviruses are enveloped viruses which include numerous human pathogens of escalating global health concern that are predominantly transmitted by mosquitoes and ticks. They 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. We have developed “virtual flavivirus” models (Figure 1) that have been used to elucidate key molecular events associated with infection and antibody recognition [1]. For example, we recently studied the phenomenon by which dengue virus particles can switch from a “smooth” to “bumpy” shaped morphology when transmitted from mosquito to human, which we hypothesize can be modulated by mutations thar arise in the envelope protein to evade host immunity by burying vulnerable epitopes. Importantly, we have shown that sufficiently strong antibodies can “outsmart” such adaptations to uncover partially buried epitope sites and neutralize the virus [2]. This shows the importance of selecting high affinity antibodies that can neutralize diverse dengue morphologies in a therapeutic setting. Leveraging on these insights, as part of a collaborative team across Duke-NUS and A*STAR recently funded by an NRF CRP grant, we are pursuing mRNA-based vaccine development to target dengue.
Some flaviviruses such as dengue exhibit a phenomenon known as antibody-dependent enhancement (ADE), in which a first infection produces antibodies specific against one viral strain, which then imperfectly cross-react with another strain during a subsequent infection. This can complicate traditional vaccinebased approaches to protection against such viruses. As an alternative, the pH-dependent conformational change of the envelope protein required for viral fusion and cellular infection is an attractive point of inhibition by antivirals. To this end, we have recently developed a computational platform to model the flavivirus “raft” as a realistic representation of the viral envelope, enabling probing via drug-like moieties such as benzene to search for hidden, druggable pockets (Figure 1). This approach has been systematically applied to six flaviviral rafts, including dengue, Yellow Fever, and Zika, and revealed a novel, highly conserved cryptic pocket. This pocket was shown to control the pH-sensing mechanism required for fusion and is now being pursued as a potential site for drug targeting and inhibition of the early stages of the viral life cycle [3].
We are leveraging the methods we have developed for flaviviruses to other enveloped viruses including SARS‑CoV‑2, prompted by the COVID-19 pandemic. Supported by an ID HTPO Seed Fund award, we have extensively characterized the structure and dynamics of the SARS-CoV-2 spike protein which covers the pathogen’s surface and is crucial for infection. We have computationally mapped the glycan coating of the spike protein as part of a global collaboration [4-5], showing that constructs derived from different labs are highly similar and closely resemble their viral counterpart. This helps to rationalize the current success of spike-based vaccines targeting SARSCoV- 2 and supports our ongoing surveillance of emerging variants of concern to assess possible effects of mutations upon function or vaccine escape.
At the same time, our computational efforts are providing new functional insights into the spike protein, its role in serious disease, and possible novel therapeutic routes. For example, we discovered with collaborators at BII [6] and NUS [7] that allostery is likely to be vital for both the viral infection process and the emergence of new variants, whilst computational probing of the spike glycoprotein surface has helped us to uncover potentially druggable pockets [8]. As well as being able to bind host factors, in collaboration with researchers at Lund University we have shown that some of these pockets represent high-affinity sites for lipopolysaccharide (LPS) molecules derived from the outer membranes of Gram-negative bacteria [9] (Figure 2). LPS serves as a signal of bacterial infection upon recognition by Tolllike receptor 4 (TLR4) of the innate immune system, but this can also result in over-amplified immune reactions and sepsis. A multidisciplinary approach [10] has elucidated the mechanism by which spike augments hyperinflammation, acting as a conduit in the TLR4 pathway to “boost” innate immune activation (Figure 2). Furthermore, we have extended these studies to also show how LPS can trigger spike protein aggregation in a physiological setting [11]. Collectively, our findings highlight the potential impact of elevated LPS levels in susceptible patients such as those with metabolic disease and Gram-negative bacterial coinfections in severe COVID-19 complications.
Antimicrobial resistance (AMR) is a leading cause of death worldwide, and there is an urgent need to discover new ways to treat bacterial infections. A multiscale simulation approach can provide an improved understanding of bacterial envelope structure and function [12-13] and contribute towards the development of novel molecules to overcome AMR. We are pursuing a broad range of novel antibacterial therapeutic routes including synthetic cyclic beta-hairpin peptides [14] in collaboration with NUS, endogenous host defence proteins [15] in collaboration with Lund University, and novel classes of antibiotics that interfere with the Gram-negative outer membrane protein assembly machinery [16] in collaboration with the University of Basel. Furthermore, Tuberculosis (TB) kills more people worldwide than any other bacterial infectious disease, and antibiotic resistance is a growing problem affecting its treatment. There has been a recent resurgence of TB drug discovery activities, leading to identification of novel enzyme inhibitors including those that block the essential F-ATP synthase (Figure 3). In collaboration with NTU, we recently elucidated the mechanisms of action of several such inhibitors [17], providing a framework which may potentially be used to develop novel lead compounds that bind to other pathogenic bacterial F-ATP synthases.
Figure 3. The ATP synthase enzyme (left) contains the c-ring turbine (green) whose rotation drives ATP synthesis. The anti-TB drug bedaquiline (BDQ) and its analogues can bind to the c-ring (right) at distinct sites (red, blue, purple) with different affinities and abilities to block catalysis.
Peter J. Bond is a Senior Principal Investigator of the Multiscale Simulation, Modeling and Design (MSMD) group at the Bioinformatics Institute (BII) A*STAR, Singapore, and Adjunct Associate Professor at the National University of Singapore (NUS). His research interests include host-pathogen interactions, receptor signaling, and virus dynamics. Following his graduation in Biochemistry at the University of Oxford in 2001, Peter moved to the Laboratory of Molecular Biophysics to read for a DPhil, supported by a Wellcome Trust Prize Studentship, and was subsequently awarded an EMBO Long-Term Fellowship hosted at the Max Planck Institute of Biophysics in Frankfurt. In 2010, he became a University Lecturer at the University of Cambridge, before moving to Singapore in late 2013.
From groundbreaking discoveries to cutting-edge research, our researchers are empowering the next generation of female science, technology, engineering and mathematics (STEM) leaders. Get inspired by our #WomeninSTEM