ABSTRACT
The dynamic structures and varying functions of intrinsically disordered proteins (IDPs) have made them fascinating subjects in molecular biology. Investigating IDP abundance in different bacterial species is crucial for understanding adaptive strategies in diverse environments. Notably, thermophilic bacteria have lower IDP abundance than mesophiles, and a negative correlation with optimal growth temperature (OGT) has been observed. However, the factors driving these trends are yet to be fully understood. We examined the types of IDPs present in both mesophiles and thermophiles alongside those unique to just mesophiles. The shared group of IDPs exhibits similar disorder levels in the two groups of species, suggesting that certain IDPs unique to mesophiles may contribute to the observed decrease in IDP abundance as OGT increases. Subsequently, we used quasi-independent contrasts to explore the relationship between OGT and IDP abundance evolution. Interestingly, we found no significant relationship between OGT and IDP abundance contrasts, suggesting that the evolution of lower IDP abundance in thermophiles may not be solely linked to OGT. This study provides a foundation for future research into the intricate relationship between IDP evolution and environmental adaptation. Our findings support further research on the adaptive significance of intrinsic disorder in bacterial species.
Subject(s)
Intrinsically Disordered Proteins , Humans , Intrinsically Disordered Proteins/chemistry , Temperature , Bacteria/genetics , Bacteria/metabolism , Protein ConformationABSTRACT
Tubulin isotypes are known to regulate microtubule stability and dynamics, as well as to play a role in the development of resistance to microtubule-targeted cancer drugs. Griseofulvin is known to disrupt cell microtubule dynamics and cause cell death in cancer cells through binding to tubulin protein at the taxol site. However, the detailed binding mode involved molecular interactions, and binding affinities with different human ß-tubulin isotypes are not well understood. Here, the binding affinities of human ß-tubulin isotypes with griseofulvin and its derivatives were investigated using molecular docking, molecular dynamics simulation, and binding energy calculations. Multiple sequence analysis shows that the amino acid sequences are different in the griseofulvin binding pocket of ßI isotypes. However, no differences were observed at the griseofulvin binding pocket of other ß-tubulin isotypes. Our molecular docking results show the favorable interaction and significant affinity of griseofulvin and its derivatives toward human ß-tubulin isotypes. Further, molecular dynamics simulation results show the structural stability of most ß-tubulin isotypes upon binding to the G1 derivative. Taxol is an effective drug in breast cancer, but resistance to it is known. Modern anticancer treatments use a combination of multiple drugs to alleviate the problem of cancer cells resistance to chemotherapy. Our study provides a significant understanding of the involved molecular interactions of griseofulvin and its derivatives with ß-tubulin isotypes, which may help to design potent griseofulvin analogues for specific tubulin isotypes in multidrug-resistance cancer cells in future.
Subject(s)
Griseofulvin , Tubulin , Humans , Tubulin/metabolism , Griseofulvin/analysis , Molecular Docking Simulation , Binding Sites , Microtubules , Paclitaxel/pharmacologyABSTRACT
Majority of protein structure studies use Escherichia coli (E. coli) and other model organisms as expression systems for other species' genes. However, protein folding depends on cellular environment factors, such as chaperone proteins, cytoplasmic pH, temperature, and ionic concentrations. Because of differences in these factors, especially temperature and chaperones, native proteins in organisms such as extremophiles may fold improperly when they are expressed in mesophilic model organisms. Here we present a methodology of assessing the effects of using E. coli as the expression system on protein structures. We compare these effects between eight mesophilic bacteria and Thermus thermophilus (T. thermophilus), a thermophile, and found that differences are significantly larger for T. thermophilus. More specifically, helical secondary structures in T. thermophilus proteins are often replaced by coil structures in E. coli. Our results show unique directionality in misfolding when proteins in thermophiles are expressed in mesophiles. This indicates that extremophiles, such as thermophiles, require unique protein expression systems in protein folding studies.
ABSTRACT
Since the outset of COVID-19, the pandemic has prompted immediate global efforts to sequence SARS-CoV-2, and over 450â¯000 complete genomes have been publicly deposited over the course of 12 months. Despite this, comparative nucleotide and amino acid sequence analyses often fall short in answering key questions in vaccine design. For example, the binding affinity between different ACE2 receptors and SARS-COV-2 spike protein cannot be fully explained by amino acid similarity at ACE2 contact sites because protein structure similarities are not fully reflected by amino acid sequence similarities. To comprehensively compare protein homology, secondary structure (SS) analysis is required. While protein structure is slow and difficult to obtain, SS predictions can be made rapidly, and a well-predicted SS structure may serve as a viable proxy to gain biological insight. Here we review algorithms and information used in predicting protein SS to highlight its potential application in pandemics research. We also showed examples of how SS predictions can be used to compare ACE2 proteins and to evaluate the zoonotic origins of viruses. As computational tools are much faster than wet-lab experiments, these applications can be important for research especially in times when quickly obtained biological insights can help in speeding up response to pandemics.