Biology subjects

Bozic, A.

Publications and source records attributed to Bozic, A..

6 recordsLinked to original sources

bioRxiv2024

Increased preference for lysine over arginine in spike proteins of SARS-CoV-2 BA.2.86 variant and its sublineages

The COVID-19 pandemic offered an unprecedented glimpse into the evolution of its causative virus, SARS-CoV-2. It has been estimated that since its outbreak in late 2019, the virus has explored all possible alternatives in terms of missense mutations for all sites of its polypeptide chain. Spike protein of the virus exhibits the largest sequence variation in particular, with many individual mutations impacting target recognition, cellular entry, and endosomal escape of the virus. Moreover, recent studies unveiled a significant increase in the total charge on the spike protein during the evolution of the virus in the initial period of the pandemic. While this trend has recently come to a halt, we perform a sequence-based analysis of the spike protein of 2665 SARS-CoV-2 variants which shows that mutations in ionizable amino acids continue to occur with the newly emerging variants, with notable differences between lineages from different clades. What is more, we show that within mutations of amino acids which can acquire positive charge, the spike protein of SARS-CoV-2 exhibits a prominent preference for lysine residues over arginine residues. This lysine-to-arginine ratio increased at several points during spike protein evolution, most recently with BA.2.86 and its sublineages, including the recently dominant JN.1, KP.3, and XEC variants. The increased ratio is a consequence of mutations in different structural regions of the spike protein and is now among the highest among viral species in the Coronaviridae family. The impact of high lysine-to-arginine ratio in the spike proteins of BA.2.86 and its daughter lineages on viral fitness remains unclear; we discuss several potential mechanisms that could play a role and that can serve as a starting point for further studies.

bioinformatics↗

bioRxiv2024

Context-dependent structure formation of RNA hairpin motifs

Many functions of ribonucleic acid (RNA) rely on its ability to assume specific sequence-structure motifs. Packaging signals found in certain RNA viruses are one such prominent example of functional RNA motifs. These signals are short hairpin loops that interact with coat proteins and drive viral self-assembly. As they are found in different positions along the much longer genomic RNA, the formation of their correct structure occurs as a part of a larger context. Any changes to this context can consequently lead to changes in the structure of the motifs themselves. In fact, previous studies have shown that structure and function of RNA motifs can be highly context-sensitive to the flanking sequence surrounding them. However, in what ways different flanking sequences influence the structure of an RNA motif they surround has yet to be studied in detail. We focus on a hairpin-rich region of the RNA genome of bacteriophage MS2--a well-studied RNA virus with a wide potential for use in biotechnology--and systematically examine context-dependent structural stability of 14 previously identified hairpin motifs, which include putative and confirmed packaging signals. Combining secondary and tertiary RNA structure prediction of the hairpin motifs placed in different contexts, ranging from the native genomic sequence to random RNA sequences and unstructured poly-U sequences, we determine different measures of motif structural stability. In this way, we show that while some motif structures can be stable in any context, others require specific context provided by the genome. Our results demonstrate the importance of context in RNA structure formation and how changes in the flanking sequence of an RNA motif sometimes lead to drastic changes in its structure. Structural stability of a motif in different contexts could provide additional insights into its functionality as well as assist in determining whether it remains functional when intentionally placed in other contexts. STATEMENT OF SIGNIFICANCERNA motifs are groups of related RNAs that possess similar sequence and/or structure and consequently assume similar functions. Despite their similarities, these motifs are often only a small part of larger RNA molecules, situated in various contexts provided by the surrounding (flanking) sequences. How the nature of the flanking sequence influences the structure of a motif it surrounds is a fundamental yet underexplored question. We systematically study context dependence of several hairpin motifs in the genomic RNA of bacteriophage MS2 which act as packaging signals, indispensable for virus assembly. We show that while some motifs fold into the correct structure no matter the nature of their context, others require the specific context provided by the genomic RNA.

biophysics↗

bioRxiv2023

Changes in total charge on spike protein of SARS-CoV-2 in emerging lineages

MotivationCharged amino acid residues on the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been shown to influence its binding to different cell surface receptors, its non-specific electrostatic interactions with the environment, and its structural stability and conformation. It is therefore important to obtain a good understanding of amino acid mutations that affect the total charge on the spike protein which have arisen across different SARS-CoV-2 lineages during the course of the virus evolution. ResultsWe analyse the change in the number of ionizable amino acids and the corresponding total charge on the spike proteins of almost 2200 SARS-CoV-2 lineages that have emerged over the span of the pandemic. Our results show that the previously observed trend toward an increase in the positive charge on the spike protein of SARS-CoV-2 variants of concern has essentially stopped with the emergence of the early omicron variants. Furthermore, recently emerged lineages show a greater diversity in terms of their composition of ionizable amino acids. We also demonstrate that the patterns of change in the number of ionizable amino acids on the spike protein are characteristic of related lineages within the broader clade division of the SARS-CoV-2 phylogenetic tree. Due to the ubiquity of electrostatic interactions in the biological environment, our findings are relevant for a broad range of studies dealing with the structural stability of SARS-CoV-2 and its interactions with the environment. AvailabilityThe data underlying the article are available in the online Supplementary Material.

bioinformatics↗

bioRxiv2023

Evolutionary changes in the number of dissociable amino acids on spike proteins and nucleoproteins of SARS-CoV-2 variants

The spike protein of SARS-CoV-2 is responsible for target recognition, cellular entry, and endosomal escape of the virus. At the same time, it is the part of the virus which exhibits the greatest sequence variation across the many variants which have emerged during its evolution. Recent studies have indicated that with progressive lineage emergence, the positive charge on the spike protein has been increasing, with certain positively charged amino acids improving the binding of the spike protein to cell receptors. We have performed a detailed analysis of dissociable amino acids of more than 1400 different SARS-CoV-2 lineages which confirms these observations while suggesting that this progression has reached a plateau with omicron and its subvariants and that the positive charge is not increasing further. Analysis of the nucleocapsid protein shows no similar increase of positive charge with novel variants, which further indicates that positive charge of the spike protein is being evolutionarily selected for. Furthermore, comparison with the spike proteins of known coronaviruses shows that already the wild-type SARS-CoV-2 spike protein carries an unusually large amount of positively charged amino acids when compared to most other betacoronaviruses. Our study sheds a light on the evolutionary changes in the number of dissociable amino acids on the spike protein of SARS-CoV-2, complementing existing studies and providing a stepping stone towards a better understanding of the relationship between the spike protein charge and viral infectivity and transmissibility.

biophysics↗

bioRxiv2021

RNA secondary structure regulates fragments' adsorption onto flat substrates

RNA is a functionally rich molecule with multilevel, hierarchical structures whose role in the adsorption to molecular substrates is only beginning to be elucidated. Here, we introduce a multiscale simulation approach that combines a tractable coarse-grained RNA structural model with an interaction potential of a structureless flat adsorbing substrate. Within this approach, we study the specific role of stem-hairpin and multibranch RNA secondary structure motifs on its adsorption phenomenology. Our findings identify a dual regime of adsorption for short RNA fragments with and without secondary structure, and underline the adsorption efficiency in both cases as a function of the surface interaction strength. The observed behavior results from an interplay between the number of contacts formed at the surface and the conformational entropy of the RNA molecule. The adsorption phenomenology of RNA seems to persist also for much longer RNAs as qualitatively observed by comparing the trends of our simulations with a theoretical approach based on an ideal semiflexible polymer chain.

biophysics↗

bioRxiv2021

Mechanics of inactive swelling and bursting of porate pollen grains

The mechanical structure of pollen grains, typically characterized by soft apertures in an otherwise stiff exine shell, guides their response to changes in the humidity of the environment. These changes can lead both to infolding but also to excessive swelling and even bursting of pollen grains. We use an elastic model to explore the mechanics of pollen grain swelling and the role that soft, circular apertures (pores) play in this process. We identify and explore a mechanical weakness of the pores, which are prone to a rapid inflation once the grain swells to a critical extent. This transition leads to the bursting of the grain and the release of its content. Our results shed light on the inactive part of the mechanical response of pollen grains to hydration once they land on a stigma as well as on bursting of airborne pollen grains during rapid changes in air humidity.

biophysics↗