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1. Impact of the lipid bilayer on energy transfer kinetics in the photosynthetic protein LH2

   https://doi.org/10.1039/C7SC04814A  

   Ogren, John I.; Tong, Ashley L.; Gordon, Samuel C.; Chenu, Aurélia; Lu, Yue; Blankenship, Robert E.; Cao, Jianshu; Schlau-Cohen, Gabriela S. (January 2018, Chemical Science)

   null (Ed.)

   Photosynthetic purple bacteria convert solar energy to chemical energy with near unity quantum efficiency. The light-harvesting process begins with absorption of solar energy by an antenna protein called Light-Harvesting Complex 2 (LH2). Energy is subsequently transferred within LH2 and then through a network of additional light-harvesting proteins to a central location, termed the reaction center, where charge separation occurs. The energy transfer dynamics of LH2 are highly sensitive to intermolecular distances and relative organizations. As a result, minor structural perturbations can cause significant changes in these dynamics. Previous experiments have primarily been performed in two ways. One uses non-native samples where LH2 is solubilized in detergent, which can alter protein structure. The other uses complex membranes that contain multiple proteins within a large lipid area, which make it difficult to identify and distinguish perturbations caused by protein–protein interactions and lipid–protein interactions. Here, we introduce the use of the biochemical platform of model membrane discs to study the energy transfer dynamics of photosynthetic light-harvesting complexes in a near-native environment. We incorporate a single LH2 from Rhodobacter sphaeroides into membrane discs that provide a spectroscopically amenable sample in an environment more physiological than detergent but less complex than traditional membranes. This provides a simplified system to understand an individual protein and how the lipid–protein interaction affects energy transfer dynamics. We compare the energy transfer rates of detergent-solubilized LH2 with those of LH2 in membrane discs using transient absorption spectroscopy and transient absorption anisotropy. For one key energy transfer step in LH2, we observe a 30% enhancement of the rate for LH2 in membrane discs compared to that in detergent. Based on experimental results and theoretical modeling, we attribute this difference to tilting of the peripheral bacteriochlorophyll in the B800 band. These results highlight the importance of well-defined systems with near-native membrane conditions for physiologically-relevant measurements. 

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2. Influenza AM2 Channel Oligomerization Is Sensitive to Its Chemical Environment

   https://doi.org/10.1021/acs.biochem.2c00160  

   Townsend, Julia A; Sanders, Henry M.; Prell, James S.; Wang, Jun; Marty, Michael T. (November 2021, Analytical chemistry)

   Sweedler, J. V. (Ed.)

   Viroporins are small viral ion channels that play important roles in the viral infection cycle and are proven antiviral drug targets. Matrix protein 2 from influenza A (AM2) is the best-characterized viroporin, and the current paradigm is that AM2 forms monodisperse tetramers. Here, we used native mass spectrometry and other techniques to characterize the oligomeric state of both the full-length and transmembrane (TM) domain of AM2 in a variety of different pH and detergent conditions. Unexpectedly, we discovered that AM2 formed a range of different oligomeric complexes that were strongly influenced by the local chemical environment. Native mass spectrometry of AM2 in nanodiscs with different lipids showed that lipids also affected the oligomeric states of AM2. Finally, nanodiscs uniquely enabled the measurement of amantadine binding stoichiometries to AM2 in the intact lipid bilayer. These unexpected results reveal that AM2 can form a wider range of oligomeric states than previously thought possible, which may provide new potential mechanisms of influenza pathology and pharmacology. 

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3. Lipid-Mediated Modulation of mGluR2 Embedded in Micelle and Bilayer Environments: Insights from Molecular Dynamics

   https://doi.org/10.1101/2025.04.06.647485  

   Khodadadi, Ehsaneh; badiee, Shadi A; Khodadadi, Ehsan; Moradi, Mahmoud (April 2025, bioRxiv)

   Abstract Metabotropic glutamate receptor 2 (mGluR2), a subclass C member of the G protein-coupled receptor (GPCR) superfamily, is essential for regulating neurotransmitter signaling and facilitating synaptic adaptability in the central nervous system. This receptor, like other GPCRs, is highly sensitive to its surrounding lipid environment, where specific lipid compositions can influence its stability, conformational dynamics, and function. In particular, cholesteryl hemisuccinate (CHS) plays a critical role in stabilizing mGluR2 and modulating its structural states within cellular membranes and micellar environments. However, the molecular basis for this lipid-mediated modulation remains largely unexplored. To investigate the effects of CHS and lipid composition on mGluR2, we employed all-atom molecular dynamics simulations of mGluR2 embedded in both detergent micelles (BLMNG and CHS) and a POPC lipid bilayer containing 0%, 10%, and 25% CHS. These simulations were conducted for both active and inactive states of the receptor. Our findings reveal that CHS concentration modulates mGluR2’s structural stability and conformational behavior, with a marked impact observed within transmembrane helices TM1, TM2, and TM3, which constitute the core of the receptor’s transmembrane domain. In micelle environments, mGluR2 displayed unique conformational dynamics influenced by CHS, underscoring the receptor’s sensitivity to its lipid surroundings. Notably, a CHS concentration of 10% elicited more pronounced conformational changes than either cholesterol-depleted (0%) or cholesterol-enriched (25%) systems, indicating an optimal CHS range for maintaining structural stability. Our study provides atomistic insights into how lipid composition and CHS concentration impact mGluR2’s conformational landscape in distinct micelle and bilayer environments. These findings advance our understanding of lipid-mediated modulation in GPCR function, highlighting potential avenues for receptor-targeted drug design, particularly in cases where lipid interactions play a significant role in therapeutic efficacy. 

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4. Protein unfolding by SDS: the microscopic mechanisms and the properties of the SDS-protein assembly

   https://doi.org/10.1039/c9nr09135a  

   Winogradoff, David; John, Shalini; Aksimentiev, Aleksei (March 2020, Nanoscale)

   The effects of detergent sodium dodecyl sulfate (SDS) on protein structure and dynamics are fundamental to the most common laboratory technique used to separate proteins and determine their molecular weights: polyacrylamide gel electrophoresis. However, the mechanism by which SDS induces protein unfolding and the microstructure of protein–SDS complexes remain largely unknown. Here, we report a detailed account of SDS-induced unfolding of two proteins—I27 domain of titin and β-amylase—obtained through all-atom molecular dynamics simulations. Both proteins were found to spontaneously unfold in the presence of SDS at boiling water temperature on the time scale of several microseconds. The protein unfolding was found to occur via two distinct mechanisms in which specific interactions of individual SDS molecules disrupt the protein's secondary structure. In the final state of the unfolding process, the proteins are found to wrap around SDS micelles in a fluid necklace-and-beads configuration, where the number and location of bound micelles changes dynamically. The global conformation of the protein was found to correlate with the number of SDS micelles bound to it, whereas the number of SDS molecules directly bound to the protein was found to define the relaxation time scale of the unfolded protein. Our microscopic characterization of SDS–protein interactions sets the stage for future refinement of SDS–enabled protein characterization methods, including protein fingerprinting and sequencing using a solid-state nanopore. 

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5. Detergents alter the stability and lipid binding properties of the CD1d immunoreceptor

   https://doi.org/10.1002/pro.70417  

   Miles, Uri Z; Finn, M G; McShan, Andrew C (January 2026, Protein Science)

   Abstract CD1d, a non‐classical immunoreceptor, plays a central role in lipid antigen presentation to a variety of T cell types. Despite the widespread use of detergents to measure and manipulate lipid/CD1d interactions in vitro, in situ, and in vivo, the molecular basis by which detergents influence the stability of CD1d and its lipid binding properties remains poorly understood. We evaluated the ability of human CD1d to associate with a panel of 13 structurally and chemically diverse detergents spanning non‐ionic, anionic, cationic, and zwitterionic classes. Through conventional intrinsic tryptophan fluorescence binding assays, complemented by the application of microscale thermophoresis and nano differential scanning fluorimetry, we quantified detergent/CD1d binding affinities and evaluated their impact on CD1d thermal stability. In silico modeling with the machine learning‐based tool Chai‐1 provided plausible detergent binding modes, which mirror docking orientations observed for native lipid ligands within the antigen binding groove. High‐affinity detergents were shown to exhibit the capacity to block lipid binding in a lipid‐dependent manner, implicating features that modulate access to the CD1d groove. These findings provide mechanistic insights into detergent‐mediated modulation of CD1d structure, stability, and function, and offer a quantitative framework for optimizing lipid‐loading protocols, detergent extraction approaches, and lipid antigen‐based immunological assays. 

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