Page 73 - CSIR-IGIB Annual Report 2020-21
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In silico autophagy principles, if any, that confer cooperativity in
Autophagy is a degradative cellular process. multimerization.
activated by several stress signals. Activation
involves a marked increase in membrane-bound Structural understanding of SARS-CoV-2
abundance of LC3 molecules on phagophore variants
membranes. Once they are recruited on the The synergy between computational tools and
membrane, other homologs carry out biological experiments is essential to elaborate
independent functions to orchestrate functions of novel SARS-CoV-2 that has costed
autophagosome formation. No detailed millions of lives in the current pandemic. The
knowledge is available about how these biomolecular dynamics on fast-timescale
homologs carry out non-redundant functions achieved via physics-based compute may help
and how these functions arose during evolution. in meeting the challenge of identifying potent
We have previously used multi-scale molecular therapeutics and cautioning for future immune-
simulations to understand how LC3 protein is escape variants. The structural understanding of
recruited onto membrane. Computational SARS-CoV-2 proteins is accelerating at an
molecular simulations provide insights into the unprecedented pace, with marked expansion of
mechanisms underlying protein dynamics three-dimensional structures since the onset of
wherein conformational changes play critical the pandemic in December 2019. Much of the
roles in initiation of a cellular event. Our present understanding is derived from key
previous simulations examined the structurally proteins that elicit neutralising antibodies,
similar homologs of LC3 and GABARAP including spike protein that forms the first layer
subfamilies in humans, investigating their of viral-host interaction. With this background,
binding modes and protein dynamics. two focus points are presented. Mapping of
Understanding their conformational behavior south-east Asia specific mutations onto SARS-
allowed us to elaborate on common features CoV2 genome; and extensive structural
and striking perturbation within binding characterisation of Spike protein using high-
regions. For instance, residues at recognition performance computing. The notable features
positions in the hydrophobic pocket of these of spike protein are its massive size, widely
family members exhibited unique specificities observed cone-shaped appearance, and striking
that may directly modulate their interaction ability to bind to host cells. Despite the high
preferences. Subsequently, we also mapped similarity in features with other viral spike
large-scale genomic variations of LC3 family proteins, sequence changes in the host-
members to propose high-frequency amino- receptor binding region (RBD domain) of SARS-
acid changes within the functional sites. Our Cov-2 are prominent. Our present efforts with
findings established structural mechanisms that structural modeling have enabled us to obtain
distinguished two broader subfamilies, LC3 and atomistically-detailed structures of Spike
GABARAP, and their roles in identifying binding proteins in the membrane. More importantly,
partners. Overall, autophagy is primarily a simulations of key mutations were studied in
membrane-driven process. The core-autophagic the light of vaccine development. In addition,
proteins are assembled onto nascent we have identified protein locations within
phagophore membrane that elongate to form SARS-CoV-2 genomes and contributed protein
double-membrane vesicles called annotation dataset to experimental datasets.
autophagosomes. We are focused on Several ongoing initiatives in this direction in
understanding how these multimeric complexes consolidating large-scale biological data on
in autophagy drive membrane elongation and spike protein and its structural modulations may
biogenesis and if we could establish general be useful in predicting trajectory of the current
pandemic.
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