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1. Unraveling the role of physicochemical differences in predicting protein–protein interactions

   https://doi.org/10.1063/5.0219501  

   Teimouri, Hamid; Medvedeva, Angela; Kolomeisky, Anatoly B (July 2024, The Journal of Chemical Physics)

   The ability to accurately predict protein–protein interactions is critically important for understanding major cellular processes. However, current experimental and computational approaches for identifying them are technically very challenging and still have limited success. We propose a new computational method for predicting protein–protein interactions using only primary sequence information. It utilizes the concept of physicochemical similarity to determine which interactions will most likely occur. In our approach, the physicochemical features of proteins are extracted using bioinformatics tools for different organisms. Then they are utilized in a machine-learning method to identify successful protein–protein interactions via correlation analysis. It was found that the most important property that correlates most with the protein–protein interactions for all studied organisms is dipeptide amino acid composition (the frequency of specific amino acid pairs in a protein sequence). While current approaches often overlook the specificity of protein–protein interactions with different organisms, our method yields context-specific features that determine protein–protein interactions. The analysis is specifically applied to the bacterial two-component system that includes histidine kinase and transcriptional response regulators, as well as to the barnase–barstar complex, demonstrating the method’s versatility across different biological systems. Our approach can be applied to predict protein–protein interactions in any biological system, providing an important tool for investigating complex biological processes’ mechanisms. 

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2. Temperature-responsive membrane permeability of recombinant fusion protein vesicles

   https://doi.org/10.1039/D3SM00096F  

   Powers, Jackson; Jang, Yeongseon (May 2023, Soft Matter)

   In this study, we investigate the changes in the permeability of the recombinant fusion protein vesicles with different membrane structures as a function of solution temperature. The protein vesicles are self-assembled from recombinant fusion protein complexes composed of an mCherry fused with a glutamic acid-rich leucine zipper and a counter arginine-rich leucine zipper fused with an elastin-like polypeptide (ELP). We have found that the molecular weight cut-off (MWCO) of the protein vesicle membranes varies inversely with solution temperature by monitoring the transport of fluorescent-tagged dextran dyes with different molecular weights. The temperature-responsiveness of the protein vesicle membranes is obtained from the lower critical solution temperature behavior of ELP in the protein building blocks. Consequently, the unique vesicle membrane structures with different single-layered and double-layered ELP organizations impact the sensitivity of the permeability responses of the protein vesicles. Single-layered protein vesicles with the ELP domains facing the interior show more drastic permeability changes as a function of temperature than double-layered protein vesicles in which ELP blocks are buried inside the membranes. This work about the temperature-responsive membrane permeability of unique protein vesicles will provide design guidelines for new biomaterials and their applications, such as drug delivery and synthetic protocell development. 

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3. Structure and dynamics determine G protein coupling specificity at a class A GPCR

   https://doi.org/10.1101/2024.03.28.587240  

   Casiraghi, Marina; Wang, Haoqing; Brennan, Patrick; Habrian, Chris; Hubner, Harald; Schmidt, Maximilian F; Maul, Luis; Pani, Biswaranjan; Bahriz, Sherif MFM; Xu, Bing; et al (March 2024, bioRxiv)

   G protein coupled receptors (GPCRs) exhibit varying degrees of selectivity for different G protein isoforms. Despite the abundant structures of GPCR-G protein complexes, little is known about the mechanism of G protein coupling specificity. The β2-adrenergic receptor is an example of GPCR with high selectivity for Gαs, the stimulatory G protein for adenylyl cyclase, and much weaker for the Gαi family of G proteins inhibiting adenylyl cyclase. By developing a new Gαi-biased agonist (LM189), we provide structural and biophysical evidence supporting that distinct conformations at ICL2 and TM6 are required for coupling of the different G protein subtypes Gαs and Gαi. These results deepen our understanding of G protein specificity and bias and can accelerate the design of ligands that select for preferred signaling pathways. 

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4. HDXBoxeR: An R package for statistical analysis and visualization of multiple Hydrogen-Deuterium Exchange Mass-Spectrometry datasets of different protein states

   https://doi.org/10.1093/bioinformatics/btae479  

   Janowska, Maria K; Reiter, Katherine; Magala, Pearl; Guttman, Miklos; Klevit, Rachel E (July 2024, Bioinformatics)

   Elofsson, Arne (Ed.)

   Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS) is a powerful protein characterization technique that provides insights into protein dynamics and flexibility at the peptide level. However, analyzing HDX-MS data presents a significant challenge due to the wealth of information it generates. Each experiment produces data for hundreds of peptides, often measured in triplicate across multiple time points. Comparisons between different protein states create distinct datasets containing thousands of peptides that require matching, rigorous statistical evaluation, and visualization. Our open-source R package, HDXBoxeR, is a comprehensive tool designed to facilitate statistical analysis and comparison of multiple sets among samples and time points for different protein states, along with data visualization. 

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5. Many-to-one binding by intrinsically disordered protein regions

   https://doi.org/10.1142/9789811215636_0015  

   Alterovitz, W L; Faraggi, E; Oldfield, C J; Meng, J W; Xue, B; Huang, F; Romero, P; Kloczkowski, A; Uversky, V N; Dunker, A K. (January 2020, Pacific symposium on biocomputing)

   Disordered binding regions (DBRs), which are embedded within intrinsically disordered proteins or regions (IDPs or IDRs), enable IDPs or IDRs to mediate multiple protein-protein interactions. DBR-protein complexes were collected from the Protein Data Bank for which two or more DBRs having different amino acid sequences bind to the same (100% sequence identical) globular protein partner, a type of interaction herein called many-to-one binding. Two distinct binding profiles were identified: independent and overlapping. For the overlapping binding profiles, the distinct DBRs interact by means of almost identical binding sites (herein called “similar”), or the binding sites contain both common and divergent interaction residues (herein called “intersecting”). Further analysis of the sequence and structural differences among these three groups indicate how IDP flexibility allows different segments to adjust to similar, intersecting, and independent binding pockets. 

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