UNC-45A: A potential therapeutic target for malignant tumors.

Uncoordinated mutant number-45 myosin chaperone A (UNC-45A), a protein highly conserved throughout evolution, is ubiquitously expressed in somatic cells. It is correlated with tumorigenesis, proliferation, metastasis, and invasion of multiple malignant tumors. The current understanding of the role of UNC-45A in tumor progression is mainly related to the regulation of non-muscle myosin II (NM-II).

Dynamic Simulations of Interaction of the PEG-DPPE Micelle-Encapsulated Short-Chain Ceramides with the Raft-Included Membrane.

The lipid raft subdomains in cancer cell membranes play a key role in signal transduction, biomolecule recruitment, and drug transmembrane transport. Augmented membrane rigidity due to the formation of a lipid raft is unfavorable for the entry of drugs, a limiting factor in clinical oncology. The short-chain ceramide (CER) has been reported to promote drug entry into membranes and disrupt lipid raft formation, but the underlying mechanism is not well understood.

Self-Association of ACE-2 with Different RBD Amounts: A Dynamic Simulation Perspective on SARS-CoV-2 Infection.

Transmissibility of SARS-CoV-2 initially relies on its trimeric Spike-RBDs to tether the ACE-2 on host cells, and enhanced self-association of ACE-2 engaged with Spike facilitates the viral infection. Two primary packing modes of Spike-ACE2 heteroproteins exist potentially due to discrepant amounts of RBDs loading on ACE-2, but the resultant self-association difference is inherently unclear. We used extensive coarse-grained dynamic simulations to characterize the self-association efficiency, the conformation relevance, and the molecular mechanism of ACE-2 with different RBD amounts.

Correction: Delivery mechanism of doxorubicin by PEG-DPPE micelles on membrane invasion by dynamic simulations.

Correction for 'Delivery mechanism of doxorubicin by PEG-DPPE micelles on membrane invasion by dynamic simulations' by Lina Zhao , , 2023, , 16114-16125, https://doi.org/10.1039/D2CP05946K.

Delivery mechanism of doxorubicin by PEG-DPPE micelles on membrane invasion by dynamic simulations.

Exploiting micelles of polyethylene glycol-dipalmitoylglycerophosphoethanolamine (PEG-DPPE) as a drug delivery approach is of great promise for improving therapeutic targeting and the half-lives of drugs. To optimize the micelle carriers, pending issues concerning the kinetics underlying the carrier-membrane interplay and the specific contributions of the micelle hydrophobic/hydrophilic components remain to be addressed. Relying on MARTINI coarse-grain (CG) molecular dynamics simulations, we explored the carrier-membrane fusion dynamics of PEG-DPPE micelles with different PEG repetitions in delivering doxorubicin (DOX).

Molecular basis of PIP2-dependent conformational switching of phosphorylated CD44 in binding FERM.

Association of the cellular adhesive protein CD44 and the N-terminal (FERM) domain of cytoskeleton adaptors is critical for cell proliferation, migration, and signaling. Phosphorylation of the cytoplasmic domain (CTD) of CD44 acts as an important regulator of the protein association, but the structural transformation and dynamics mechanism remain enigmatic. In this study, extensive coarse-grained simulations were employed to explore the molecular details in the formation of CD44-FERM complex under S291 and S325 phosphorylation, a modification path known to exert reciprocal effects on the protein association.

Computer-Aided Design of Lasso-like Self-Assembling Anticancer Peptides with Multiple Functions for Targeted Self-Delivery and Cancer Treatments.

Anticancer peptides are promising drug candidates for cancer treatment, but the short circulation time and low delivery efficiency limit their clinical applications. Herein, we designed several lasso-like self-assembling anticancer peptides (LASAPs) integrated with multiple functions by a computer-aided approach. Among these LASAPs, LASAP1 (CRGDKGPDCGKAFRRFLGALFKALSHLL, 1-9 disulfide bond) was determined to be superior to the others because it can self-assemble into homogeneous nanoparticles and exhibits improved stability in serum.

General mechanism of spider toxin family I acting on sodium channel Nav1.7.

Various peptide toxins in animal venom inhibit voltage-gated sodium ion channel Nav1.7, including Nav-targeting spider toxin (NaSpTx) Family I. Toxins in NaSpTx Family I share a similar structure, i.

Molecular mechanism of CD44 homodimerization modulated by palmitoylation and membrane environments.

The homodimerization of CD44 plays a key role in an intercellular-to-extracellular signal transduction and tumor progression. Acylated modification and specific membrane environments have been reported to mediate translocation and oligomerization of CD44; however, the underlying molecular mechanism remains elusive. In this study, extensive molecular dynamics simulations are performed to characterize the dimerization of palmitoylated CD44 variants in different bilayer environments.

Zafirlukast inhibits the growth of lung adenocarcinoma via inhibiting TMEM16A channel activity.

Lung cancer has the highest mortality among cancers worldwide due to its high incidence and lack of the effective cures. We have previously demonstrated that the membrane ion channel TMEM16A is a potential drug target for the treatment of lung adenocarcinoma and have identified a pocket of inhibitor binding that provides the basis for screening promising new inhibitors. However, conventional drug discovery strategies are lengthy and costly, and the unpredictable side effects lead to a high failure rate in drug development.

Molecular dynamics simulation of TMEM16A channel: Linking structure with gating.

TMEM16A, the calcium-activated chloride channel, is broadly expressed and plays pivotal roles in diverse physiological processes. To understand the structural and functional relationships of TMEM16A, it is necessary to fully clarify the structural basis of the gating of the TMEM16A channel. Herein, we performed the protein electrostatic analysis and molecular dynamics simulation on the TMEM16A in the presence and absence of Ca.

Theaflavin binds to a druggable pocket of TMEM16A channel and inhibits lung adenocarcinoma cell viability.

As a calcium-activated chloride channel regulated by the intracellular Ca concentration and membrane potential, TMEM16A has attracted considerable attention and has been proposed as a novel anticancer drug target. We have previously reported that the pocket above the ion conductance pore could be a nonselective inhibitor-binding pocket. However, whether this pocket is druggable remains unexplored.

Molecular mechanism of CaCC-A01 inhibiting TMEM16A channel.

TMEM16A is a calcium-activated chloride channel that is associate with several diseases, including pulmonary diseases, hypertension, diarrhea and cancer. The CaCC-A01 (A01) is widely recognized as an efficient blocker of TMEM16A and has been used as a tool drug to inhibit TMEM16A currents in the laboratory. A01 also has excellent pharmacokinetic properties and can be developed as a drug to target TMEM16A.

Molecular mechanism for bidirectional regulation of CD44 for lipid raft affiliation by palmitoylations and PIP2.

The co-localization of Cluster-of-Differentiation-44 protein (CD44) and cytoplasmic adaptors in specific membrane environments is crucial for cell adhesion and migration. The process is controlled by two different pathways: On the one hand palmitoylation keeps CD44 in lipid raft domains and disables the linking to the cytoplasmic adaptor, whereas on the other hand, the presence of phosphatidylinositol-4,5-biphosphate (PIP2) lipids accelerates the formation of the CD44-adaptor complex. The molecular mechanism explaining how CD44 is migrating into and out of the lipid raft domains and its dependence on both palmitoylations and the presence of PIP2 remains, however, elusive.

Molecular Mechanisms and Structural Basis of Retigabine Analogues in Regulating KCNQ2 Channel.

KCNQ2 channel is one of the important members of potassium voltage-gated channel. KCNQ2 is closely related to neuronal excitatory diseases including epilepsy and neuropathic pain, and also acts as a drug target of the anti-epileptic drug, retigabine (RTG). In the past few decades, RTG has shown strong efficacy in the treatment of refractory epilepsy but has been withdrawn from clinical use due to its multiple adverse effects in clinical phase III trials.

Low intra-abdominal pressure and deep neuromuscular blockade laparoscopic surgery and surgical space conditions: A meta-analysis.

Background: Low intra-abdominal pressure (IAP) and deep neuromuscular blockade (NMB) are frequently used in laparoscopic abdominal surgery to improve surgical space conditions and decrease postoperative pain. The evidence supporting operations using low IAP and deep NMB is open to debate.

Methods: The feasibility of the routine use of low IAP +deep NMB during laparoscopic surgery was examined.

Amyloid-Forming Segment Induces Aggregation of FUS-LC Domain from Phase Separation Modulated by Site-Specific Phosphorylation.

The RNA-binding protein fused in sarcoma (FUS) forms physiological granules and pathological fibrils, which facilitate RNA functions and cause neurodegenerative diseases, respectively. Phosphorylation at Ser/Thr residues may regulate the functional assembly of FUS and prevent pathological aggregation in cells. However, the low-complexity nature of the FUS sequence makes it challenging to characterize how phosphorylation of specific sites within the core amyloid-forming segment affects aggregation.

Molecular Dynamics of the Association of L-Selectin and FERM Regulated by PIP2.

Phosphatidylinositol 4,5-bisphosphate (PIP2) acts as a signaling lipid, mediating membrane trafficking and recruitment of proteins to membranes. A key example is the PIP2-dependent regulation of the adhesion of L-selectin to the cytoskeleton adaptors of the N-terminal subdomain of ezrin-radixin-moesin (FERM). The molecular details of the mediating behavior of multivalent anionic PIP2 lipids in this process, however, remain unclear.

The dimerization of PSGL-1 is driven by the transmembrane domain via a leucine zipper motif.

P-selectin glycoprotein ligand-1 (PSGL-1) is a homodimeric mucin ligand that is important to mediate the earliest adhesive event during an inflammatory response by rapidly forming and dissociating the selectin-ligand adhesive bonds. Recent research indicates that the noncovalent associations between the PSGL-1 transmembrane domains (TMDs) can substitute for the C320-dependent covalent bond to mediate the dimerization of PSGL-1. In this article, we combined TOXCAT assays and molecular dynamics (MD) simulations to probe the mechanism of PSGL-1 dimerization.

High-Resolution Insights into the Stepwise Self-Assembly of Nanofiber from Bioactive Peptides.

Peptide self-assembly has a profound biological significance since self-assembled bioactive peptides are gifted with improved bioactivity as well as life-span. In this study, peptide self-assembly was investigated using a therapeutic peptide, PTP-7S (EENFLGALFKALSKLL). Combining experiments of atomic force microscopy (AFM), circular dichroism (CD), and 8-anilino-1-naphthalenesulfonic acid (ANS) fluorescence spectra, PTP-7S showed the α-helical structure and was found self-assembling into nanofibers in solution.

Dimerization and Structural Stability of Amyloid Precursor Proteins Affected by the Membrane Microenvironments.

The lipid raft microenvironment is implicated in the generation of the pathological amyloid-β (Aβ) species in amyloid precursor protein (APP) that is associated with neurodegenerative diseases. Evidence shows that APP forms a transmembrane homodimer with changeable structures as a function of the membrane compositions. However, the molecular responsibility of the dimerization and structural alteration for the amyloidogenic process in segregated membranes remains largely unclear.

Insights into the transmembrane helix associations of kit ligand by molecular dynamics simulation and TOXCAT.

Kit ligand (KITL) plays important roles in cell proliferation, differentiation, and survival via interaction with its receptor Kit. The previous studies demonstrated that KITL formed a noncovalent homodimer through transmembrane (TM) domain; however, the undergoing mechanism of transmembrane association that determines KITL TM dimerization is still not clear. Herein, molecular dynamics (MD) simulation strategy and TOXCAT assay were combined to characterize the dimerization interface and structure of KITL TM in details.

Critical residues and motifs for homodimerization of the first transmembrane domain of the plasma membrane glycoprotein CD36.

The plasma transmembrane (TM) glycoprotein CD36 is critically involved in many essential signaling processes, especially the binding/uptake of long-chain fatty acids and oxidized low-density lipoproteins. The association of CD36 potentially activates cytosolic protein tyrosine kinases that are thought to associate with the C-terminal cytoplasmic tail of CD36. To understand the mechanisms by which CD36 mediates ligand binding and signal transduction, we have characterized the homo-oligomeric interaction of CD36 TM domains in membrane environments and with molecular dynamics (MD) simulations.

Role of peptide self-assembly in antimicrobial peptides.

Antimicrobial peptides (AMPs) are considered as potential antibiotic substitutes because of their potent activities. Previous studies mainly focused on the effects of peptide charges and secondary structures, but the self-assembly of AMPs was neglected. As more and more researchers notice the roles of peptide self-assembly in AMPs, it has been considered as another important property.