Biophysical chemistry最新文献

Understanding the formation of β-fibrils over the gold surface is of paramount interest in nano-bio-medicinal Chemistry. The intricate mechanism of self-assembly of neurofibrillogenic peptides and their growth over the gold surface remains elusive, as experiments are limited in unveiling the microscopic dynamic details, in particular, at the early stage of the peptide aggregation. In this work, we carried out equilibrium molecular dynamics and enhanced sampling simulations to elucidate the underlying mechanism of the growth of an amyloid-forming sequence of tau fragments over the gold surface. Our results disclose that the collective intermolecular interactions between the peptide chains and peptides with the gold surface facilitate the peptide adsorption, followed by integration, finally leading to the fibril formation.

Quantum dots (QDs) are semiconductor nanocrystals (2–10 nm) with unique optical and electronic properties due to quantum confinement effects. They offer high photostability, narrow emission spectra, broad absorption spectrum, and high quantum yields, making them versatile in various applications. Due to their highly reactive surfaces, QDs can conjugate with biomolecules while being used, produced, or unintentionally released into the environment. This systematic review delves into intricate relationship between QDs and proteins, examining their interactions that influence their physicochemical properties, enzymatic activity, ligand binding affinity, and stability. The research utilized electronic databases like PubMed, WOS, and Proquest, along with manual reviews from 2013 to 2023 using relevant keywords, to identify suitable literature. After screening titles and abstracts, only articles meeting inclusion criteria were selected for full text readings. This systematic review of 395 articles identifies 125 articles meeting the inclusion criteria, categorized into five overarching themes, encompassing various mechanisms of QDs and proteins interactions, including adsorption to covalent binding, contingent on physicochemical properties of QDs. Through a meticulous analysis of existing literature, it unravels intricate nature of interaction, significant influence on nanomaterials and biological entities, and potential for synergistic applications harnessing both specific and nonspecific interactions across various fields.

The misfolding and aggregation of human islet amyloid polypeptide (hIAPP), also known as amylin, have been implicated in the pathogenesis of type 2 diabetes (T2D). Heat shock proteins, specifically, heat shock cognate 70 (Hsc70), are molecular chaperones that protect against hIAPP misfolding and inhibits its aggregation. Nevertheless, there is an incomplete understanding of the mechanistic interactions between Hsc70 domains and hIAPP, thus limiting their potential therapeutic role in diabetes. This study investigates the inhibitory capacities of different Hsc70 variants, aiming to identify the structural determinants that strike a balance between efficacy and cytotoxicity. Our experimental findings demonstrate that the ATPase activity of Hsc70 is not a pivotal factor for inhibiting hIAPP misfolding. We underscore the significance of the C-terminal substrate-binding domain of Hsc70 in inhibiting hIAPP aggregation, emphasizing that the removal of the lid subdomain diminishes the inhibitory effect of Hsc70. Additionally, we employed atomistic discrete molecular dynamics simulations to gain deeper insights into the interaction between Hsc70 variants and hIAPP. Integrating both experimental and computational findings, we propose a mechanism by which Hsc70's interaction with hIAPP monomers disrupts protein-protein connections, primarily by shielding the β-sheet edges of the Hsc70-β-sandwich. The distinctive conformational dynamics of the alpha helices of Hsc70 potentially enhance hIAPP binding by obstructing the exposed edges of the β-sandwich, particularly at the β5-β8 region along the alpha helix interface. This, in turn, inhibits fibril growth, and similar results were observed following hIAPP dimerization. Overall, this study elucidates the structural intricacies of Hsc70 crucial for impeding hIAPP aggregation, improving our understanding of the potential anti-aggregative properties of molecular chaperones in diabetes treatment.

A novel inhibitor, carboxyphenylboronic acid-modified chitosan oligosaccharide (COS-CPBA), was developed by coupling carboxyphenylboronic acid (CPBA) with chitosan oligosaccharide (COS) to inhibit insulin fibrillation. Extensive biophysical assays indicated that COS-CPBA could decelerate insulin aggregation, hinder the conformational transition from α-helix to β-sheet structure, change the morphology of insulin aggregates and alter fibrillation pathway. A mechanism for the inhibition of insulin fibrillation by COS-CPBA was proposed. It considers that insulin molecules bind to COS-CPBA via hydrophobic interactions, while the positively charged groups in COS-CPBA exert electrostatic repulsion on the bound insulin molecules. These two opposite forces cause the insulin molecules to display extended conformations and hinder the conformational transition of insulin from α-helix to β-sheet structure necessary for fibrillation, thus decelerating aggregation and altering the fibrillation pathway of insulin. The studies provide novel ideas for the development of more effective inhibitors of amyloid fibrillation.

Activation of heterotrimeric G-proteins ($G\mathrm{\alpha \beta \gamma }$) downstream to receptor tyrosine kinases (RTKs) is a well-established crosstalk between the signaling pathways mediated by G-protein coupled receptors (GPCRs) and RTKs. While GPCR serves as a guanine exchange factor (GEF) in the canonical activation of $G\alpha$ that facilitates the exchange of GDP for GTP, the mechanism through which RTK phosphorylations induce $G\alpha$ activation remains unclear. Recent experimental studies revealed that the epidermal growth factor receptor (EGFR), a well-known RTK, phosphorylates the helical domain tyrosine residues Y154 and Y155 and accelerates the GDP release from the $G\alpha i3$, a subtype of $G\alpha$-protein. Using well-tempered metadynamics and extensive unbiased molecular dynamics simulations, we captured the GDP release event and identified the intermediates between bound and unbound states through Markov state models. In addition to weakened salt bridges at the domain interface, phosphorylations induced the unfolding of helix $\alpha F$, which contributed to increased flexibility near the hinge region, facilitating a greater distance between domains in the phosphorylated $G\alpha i3$. Although the larger domain separation in the phosphorylated system provided an unobstructed path for the nucleotide, the accelerated release of GDP was attributed to increased fluctuations in several conserved regions like P-loop, switch 1, and switch 2. Overall, this study provides atomistic insights into the activation of G-proteins induced by RTK phosphorylations and identifies the specific structural motifs involved in the process. The knowledge gained from the study could establish a foundation for targeting non-canonical signaling pathways and developing therapeutic strategies against the ailments associated with dysregulated G-protein signaling.

ATP-hydrolysis-associated conformational change of the β-subunit during the rotation of F₁-ATPase (F₁) has been discussed using cryo-electron microscopy (cryo-EM). Since it is worthwhile to further investigate the conformation of ATP at the catalytic subunit through an alternative approach, the structure of ATP bound to the F₁β-subunit monomer (β) was analyzed by solid-state NMR. The adenosine conformation of ATP-β was similar to that of ATP analog in F₁ crystal structures. ³¹P chemical shift analysis showed that the P^α and P^β conformations of ATP-β are gauche-trans and trans-trans, respectively. The triphosphate chain is more extended in ATP-β than in ATP analog in F₁ crystals. This appears to be in the state just before ATP hydrolysis. Furthermore, the ATP-β conformation is known to be more closed than the closed form in F₁ crystal structures. In view of the cryo-EM results, ATP-β would be a model of the most closed β-subunit with ATP ready for hydrolysis in the hydrolysis stroke of the F₁ rotation.

Emodin is a natural anthraquinone derivative found in nature, widely known as an herbal medicine. Here, the partition, location, and interaction of emodin with lipid membranes of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) are experimentally investigated with different techniques. Our studies have considered the neutral form of emodin (EMH) and its anionic/deprotonated form (EM⁻), and their interaction with a more and less packed lipid membrane, DMPC at the gel and fluid phases, respectively. Though DSC results indicate that the two species, EMH and EM⁻, similarly disrupt the packing of DMPC bilayers, spin labels clearly show that EMH causes a stronger bilayer disruption, both in gel and fluid DMPC. Fluorescence spectroscopy shows that both EMH and EM⁻ have a high affinity for DMPC: the binding of EM⁻ to both gel and fluid DMPC bilayers was found to be quite similar, and similar to that of EMH to gel DMPC, K_p = (1.4 ± 0.3)x10³. However, EMH was found to bind twice more strongly to fluid DMPC bilayers, K_p = (3.2 ± 0.3)x10³. Spin labels and optical absorption spectroscopy indicate that emodin is located close to the lipid bilayer surface, and suggest that EM⁻ is closer to the lipid/water interface than EMH, as expected. The present studies present a relevant contribution to the current understanding of the effect the two species of emodin, EMH and EM⁻, present on different microregions of an organism, as local pH values can vary significantly, can cause in a neutral lipid membrane, either more or less packed, liked gel and fluid DMPC, respectively, and could be extended to lipid domains of biological membranes.

Nanodisc technology is increasingly being used in structural, biochemical and biophysical studies of membrane proteins. The computational approaches have revealed many important features of nanodisc assembly, structures and dynamics. Therefore, we reviewed the application of computational approaches, especially molecular modeling and molecular dyncamics (MD) simulations, to characterize nanodiscs, including the structural models, assembly and disassembly, protocols for modeling, structural properties and dynamics, and protein-lipid interactions in nanodiscs. More amazing computational studies about nanodiscs are looked forward to in the future.

The aggregation of transactive response deoxyribonucleic acid (DNA) binding protein of 43 kDa (TDP-43) into ubiquitin-positive inclusions is closely associated with amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and chronic traumatic encephalopathy. The 370–375 fragment of TDP-43 (³⁷⁰GNNSYS³⁷⁵, TDP-43_370-375), the amyloidogenic hexapeptides, can be prone to forming pathogenic amyloid fibrils with the characteristic of steric zippers. Previous experiments reported the ALS-associated mutation, serine 375 substituted by glycine (S375G) is linked to early onset disease and protein aggregation of TDP-43. Based on this, it is necessary to explore the underlying molecular mechanisms. By utilizing all-atom molecular dynamics (MD) simulations of 102 μs in total, we investigated the impact of S375G mutation on the conformational ensembles and oligomerization dynamics of TDP-43_370-375 peptides. Our replica exchange MD simulations show that S375G mutation could promote the unstructured conformation formation and induce peptides to form a loose packed oligomer, thus inhibiting the aggregation of TDP-43_370-375. Further analyses suggest that S375G mutation displays a reduction effect on the number of total hydrogen bonds and contacts among TDP-43_370-375 peptides. Hydrogen bonding and polar interactions among TDP-43_370-375 peptides, as well as Y374-Y374 π-π stacking interaction, are attenuated by S375G mutation. Additional microsecond MD simulations demonstrate that S375G mutation could prohibit the conformational conversion to β-structure-rich aggregates and possess an inhibitory effect on the oligomerization dynamics of TDP-43_370-375. This study offers for the first time of molecular insights into the S375G mutation affecting the aggregation of TDP-43_370-375 at the atomic level, and may open new avenues in the development of future site-specific mutation therapeutics.

The study specifically investigates the solubilities of L-isoleucine and L-tyrosine in water-mixed solvent systems (DMF, DMSO, and ACN), exploring the behaviour of amino acids in complex environments. The experimental methods prioritize meticulous solvent purification to ensure reliable results. The work explores solubility data, uncovering temperature-dependent trends and intricate interactions influencing solubility in the chosen mixed solvent systems. The study emphasizes the impact of thermodynamic properties, solvent-solvent interactions, and amino acid structure on solubility patterns. The broader implications highlight the relevance of understanding amino acid behaviour in diverse solvent environments, offering potential applications in cosmetics and pharmaceutical industries. The distinct solubility patterns contribute valuable insights, enhancing on the understanding of the solution stability and interactions of L-isoleucine and L-tyrosine in different solvent systems. In conclusion, work suggests the enhanced utilization of L-isoleucine and L-tyrosine in various industries, driven by a profound understanding of their solubility in mixed solvent systems. The research expands our knowledge of amino acid behaviour, paving the way for advancements in industries relying on protein-based products and technologies.