Exploring the Regulatory Function of the N-terminal Domain of SARS-CoV-2 Spike Protein through Molecular Dynamics Simulation.

SARS-CoV-2 is what has caused the COVID-19 pandemic. Early viral infection is mediated by the SARS-CoV-2 homo-trimeric Spike (S) protein with its receptor binding domains (RBDs) in the receptor-accessible state. Molecular dynamics simulation on the S protein with a focus on the function of its N-terminal domains (NTDs) is performed. The study reveals that the NTD acts as a "wedge" and plays a crucial regulatory role in the conformational changes of the S protein. The complete RBD structural transition is allowed only when the neighboring NTD that typically prohibits the RBD's movements as a wedge detaches and swings away. Based on this NTD "wedge" model, it is proposed that the NTD-RBD interface should be a potential drug target.

Frontier Expansion Sampling: A Method to Accelerate Conformational Search by Identifying Novel Seed Structures for Restart.

Traditional molecular dynamics (MD) simulations have difficulties in tracking the slow molecular motions, at least partially due to the waste of sampling in already sampled regions. Here, we proposed a new enhanced sampling method, frontier expansion sampling (FEXS), to improve the sampling efficiency of molecular simulations by iteratively selecting seed structures diversely distributed at the "frontier" of an already sampled region to initiate new simulations. Different from other enhanced sampling methods, FEXS identifies the "frontier" seeds by integrating the Gaussian mixture model and the convex hull algorithm, which effectively improves the structural variation among the selected seeds and thus the descendant simulations. Validation in three protein systems, including the folding of chignolin, open-to-closed transition of maltodextrin binding protein, and internal conformational change of bovine pancreatic trypsin inhibitor, confirmed the effectiveness of this novel method in enhancing the sampling of conventional MD simulations to observe the large-scale protein conformational changes. When compared with other enhanced sampling methods like the structural dissimilarity sampling (SDS), FEXS reached at least the same level of sampling efficiency but was capable of providing complementary information in the three tested protein systems.

[A new guaiane-type sesquiterpenoid from Croton yunnanensis].

Five sesquiterpenoids were isolated from 90% ethanol extract of Croton yunnanensis by silica gel,Sephadex LH-20 column chromatography,as well as prep-HPLC methods. Based on MS,1 D and 2 D NMR spectral analyses,the structures of the five compounds were identified as 11-methoxyl alismol(1),6ß,7ß-epoxy-4α-hydroxyguaian-10-ene(orientalol C,2),multisalactone D(3),arvestonol(4),and 4,5-dihydroblumenol A(5). Compound 1 was a new guaiane-type sesquiterpenoid. Compounds 2-4 were isolated from the Croton genus for the first time,and compound 5 was obtained from this plant for the first time.

Bioactive glycosides from Salacia cochinchinensis.

Four new triterpene glycosides, named salaciacochinosides A-D (1-4) were isolated from the 90% ethanol extract of Salacia cochinchinensis, together with five known compounds 2α,3ß,23-trihydroxyurs-12,18-dien-28-oic acid 28-O-ß-d-glucopyranoside (5), racemiside (6), alangiplatanoside (7), acantrifoside E (8), and syringin (9). The structures of the four new triterpenoids were characterized by chemical methods and MS, IR, 1D and 2D NMR spectral analyses. The α-glucosidase inhibitory activities of the nine compounds were assessed, compounds 6 and 7 showed remarkable α-glucosidase inhibitory activities, with IC50 values of 0.44 and 0.75 µM, respectively. Compounds 1-5 exhibited moderate α-glucosidase inhibitory activities, and compounds 8 and 9 showed none α-glucosidase inhibitory activity in our current experiments.

Structure of the human voltage-gated sodium channel Nav1.4 in complex with ß1.

Voltage-gated sodium (Nav) channels, which are responsible for action potential generation, are implicated in many human diseases. Despite decades of rigorous characterization, the lack of a structure of any human Nav channel has hampered mechanistic understanding. Here, we report the cryo-electron microscopy structure of the human Nav1.4-ß1 complex at 3.2-Å resolution. Accurate model building was made for the pore domain, the voltage-sensing domains, and the ß1 subunit, providing insight into the molecular basis for Na+ permeation and kinetic asymmetry of the four repeats. Structural analysis of reported functional residues and disease mutations corroborates an allosteric blocking mechanism for fast inactivation of Nav channels. The structure provides a path toward mechanistic investigation of Nav channels and drug discovery for Nav channelopathies.

Four New Diterpene Glucosides from Perovskia atriplicifolia.

Four new diterpene glucosides, namely perovskiaditerpenosides A - D (1 - 4), were isolated from the BuOH extract of Perovskia atriplicifolia. Their structures were well elucidated by chemical methods and comprehensive spectroscopic analyses including MS, IR, and NMR (1D and 2D). The newly isolated compounds were screened for their cytotoxic activity against HepG2, NB4, HeLa, K562, MCF7, PC3, and HL60. The obtained results indicated that the new compounds possessed considerable cytotoxic activity.