Biology subjects

Ghaemi, Z.

Publications and source records attributed to Ghaemi, Z..

4 recordsLinked to original sources

bioRxiv2025

Probing the Role of Membrane in Neutralizing Activity of Antibodies Against Influenza Virus

Influenza poses a major health issue globally. Neutralizing antibodies targeting the highly conserved stem region of hemagglutinin (HA) of the influenza virus provide considerable protection against the infection. Using an array of advanced simulation technologies, we developed a high-resolution structural model of full-length, Fab-bound HA in a native viral membrane to characterize direct membrane interactions that govern the efficacy of the antibody. We reveal functionally important residues beyond the antibodys complementary-determining regions that contribute to its membrane binding. Mutagenesis experiments and infectivity assays confirm that deactivating the membrane-binding residues of the antibody decreases its neutralization activity. Therefore, we propose that the association with the viral membrane plays a key role in the neutralization activity of these antibodies. Given the rapid evolution of the influenza virus, the developed model provides a structural framework for the rational design and development of more effective therapeutic antibodies.

biophysics↗

bioRxiv2022

A Spatial Whole-Cell Model for HBV Viral Infection and Drug Interactions

Despite a vaccine, hepatitis B virus (HBV) remains a world-wide source of infections and deaths, and tackling the infection requires a multimodal approach against the virus. We develop a whole-cell computational platform combining spatial and kinetic models for the infection cycle of a virus host cell (hepatocyte) by HBV. We simulate a near complete viral infection cycle with this whole-cell platform stochastically for 10 minutes of biological time, to predict viral infection, map out virus-host as well as virus-drug interactions. We find that with an established infection, decreasing the copy number of the viral envelope proteins can shift the dominant infection pathways from secreting the capsids from the cell to re-importing the capsids back to the nucleus, resulting in higher viral DNA referred to as covalently closed circular DNA (cccDNA) copy number. This scenario can mimic the consequence of drugs designed to manipulate viral gene expression (such as siRNAs). Viral capsid mutants lead to their destabilization such that they disassemble at nuclear pore complexes, result in an increase in cccDNA copy number. However, excessive destabilization leading to cytoplasmic disassembly does not increase the cccDNA copy number. Finally, our simulations can predict the best drug dosage and timing of its administration to reduce the cccDNA copy number which is the hallmark of infection. Our adaptable computational platform can be utilized to study other viruses, more complex host-virus interactions, and identify the most central viral pathways that can be targeted by drugs or a combination of them.

systems biology↗

bioRxiv2021

Molecular Mechanism of Capsid Disassembly in Hepatitis B Virus

The disassembly of a viral capsid leading to the release of its genetic material into the host cell is a fundamental step in viral infection. Hepatitis B virus (HBV) in particular consists of identical capsid protein monomers that dimerize and also arrange themselves into pentamers or hexamers on the capsid surface. By applying atomistic molecular dynamics simulation to an entire solvated HBV capsid subject to a uniform mechanical stress protocol, we monitor the disassembly process down to the level of individual amino acids. The strain of an external force combined with thermal fluctuations causes structurally heterogeneous cracks to appear in the HBV capsid. Unlike the expectation from purely mechanical considerations, the cracks mainly occur within and between hexameric sites, whereas pentameric sites remain largely intact. Only a small subset of the capsid protein monomers governs disassembly. These monomers are distributed across the whole capsid, but belong to regions with a high degree of collective motion that we label communities. Cross-talk within these communities is a mechanism of crack propagation leading to destabilization of the entire capsid, and eventually its disassembly. We identify specific residues whose interactions are most readily lost during disassembly: R127, I139, Y132, N136, A137, and V149 are among the hotspots at the interfaces between dimers that lie within or span hexamers, leading to dissociation. The majority of these hotspots are evolutionary conserved, indicating that they are important for disassembly by avoiding over-stabilization of capsids. SignificanceHepatitis B virus (HBV) is a DNA virus that is 100 times more infectious than HIV. Despite the availability of a vaccine, the chronic infection rate of this virus is still about 300 million people globally. HBV chronic infection, for which no cure is currently available, can lead to liver cancer. Therefore, there is an unmet need to investigate the infection cycle of the virus. One of the most crucial steps in virus replication cycle is the release of its genetic material to the nucleus. During this step, the viral capsid enclosing the genetic material disassembles. However, its mechanism is unknown. Here, we utilize molecular simulations to shed light on the events leading to the capsid disassembly with atomistic detail.

biophysics↗

bioRxiv2018

An In-Silico Mammalian Whole-Cell Model Reveals the Influence of Spatial Organization on RNA Splicing Efficiency

Spatial organization is a characteristic of eukaryotic cells, achieved by utilizing both membrane-bound and non-bound organelles. We model the effects of this organization and of organelle heterogeneity on RNA splicing (the process of making translationally-ready messenger RNA) and on splicing particles (the building blocks of splicing machinery) in mammalian cells. We constructed a spatially-resolved whole HeLa cell model from various experimental data and developed reaction networks to describe the RNA splicing processes. We incorporated these networks into our whole-cell model and performed stochastic simulations for up to 15 minutes of biological time. We find that the number of nuclear pore complexes affects the number of assembled splicing particles; that a slight increase of splicing particle localization in nuclear speckles (non-membrane-bound or- ganelles) leads to disproportionate enhancement in the mRNA splicing and reduction in the transcript noise; and that compartmentalization is critical for a correctly-assembled particle yield. Our model also predicts that the distance between genes and speckles has a considerable effect on effective mRNA production rate, further emphasizing the importance of genome organization around speckles. The HeLa cell model, including organelles and subcompartments, provides an adaptable foundation to study other cellular processes which are strongly modulated by spatio-temporal heterogeneity.\n\nSignificance StatementThe spliceosome is one of the most complex cellular machineries that cuts and splices the RNA code in eukaryotic cells. It dynamically assembles, disassembles, and its components are formed in multiple compartments. The efficiency of splicing process depends on localization of its components in nuclear membrane-less organelles. Therefore, a computational model of spliceosomal function must contain a spatial model of the entire cell. However, building such a model is a challenging task, mainly due to the lack of homogeneous experimental data and a suitable computational framework. Here, we overcome these challenges and present a whole HeLa cell model, with nuclear, subnuclear, and extensive cytoplasmic structures. The three-dimensional model is supplemented by reaction-diffusion processes to shed light on the function of the spliceosome.

biophysics↗