Discovery of Staircase Chirality through the Design of Unnatural Amino Acid Derivatives.

Chirality has garnered significant attention in the scientific community since its discovery by Louis Pasteur over a century ago. It has been showing a profound impact on chemical, biomedical, and materials sciences. Significant progress has been made in controlling molecular chirality, as evidenced by the several Nobel Prizes in chemistry awarded in this area, particularly for advancements in the asymmetric catalytic synthesis of molecules with central and axial chirality.

Amino Turbo Chirality and Its Asymmetric Control.

A series of new targets containing 3 chiral elements of central, orientational, and turbo chirality have been designed and synthesized asymmetrically. The absolute configurations and conformations of these types of chirality were concurrently controlled by using chiral sulfonimine auxiliary and unambiguously determined by x-ray diffraction analysis. These targets include alpha unnatural amino acid derivatives, which may play an important role for drug design, discovery, and development.

Atomic-Level Free Energy Landscape Reveals Cooperative Symport Mechanism of Melibiose Transporter.

The Major Facilitator Superfamily (MFS) transporters are an essential class of secondary active transporters involved in various physiological and pathological processes. The melibiose permease (MelB), which catalyzes the stoichiometric symport of the disaccharide melibiose and monovalent cations (e.g.

Distinct roles of the major binding residues in the cation-binding pocket of the melibiose transporter MelB.

Salmonella enterica serovar Typhimurium melibiose permease (MelB) is a prototype of the major facilitator superfamily (MFS) transporters, which play important roles in human health and diseases. MelB catalyzed the symport of galactosides with Na, Li, or H but prefers the coupling with Na. Previously, we determined the structures of the inward- and outward-facing conformation of MelB and the molecular recognition for galactoside and Na.

Development of Parallel On-the-Fly Algorithm for Global Exploration of Conical Intersection Seam Space.

Conical intersection (CI) seams are configuration spaces of a molecular system where two or more (spin) adiabatic electronic states are degenerate in energy. They play essential roles in photochemistry because nonradiative decays often occur near the minima of the seam, i.e.

Distinct roles of the major binding residues in the cation-binding pocket of MelB.

serovar Typhimurium melibiose permease (MelB) is a prototype of the major facilitator superfamily (MFS) transporters, which play important roles in human health and diseases. MelB catalyzed the symport of galactosides with either H, Li, or Na, but prefers the coupling with Na. Previously, we determined the structures of the inward- and outward-facing conformation of MelB, as well as the molecular recognition for galactoside and Na.

Mobile barrier mechanisms for Na-coupled symport in an MFS sugar transporter.

While many 3D structures of cation-coupled transporters have been determined, the mechanistic details governing the obligatory coupling and functional regulations still remain elusive. The bacterial melibiose transporter (MelB) is a prototype of major facilitator superfamily transporters. With a conformation-selective nanobody, we determined a low-sugar affinity inward-facing Na-bound cryoEM structure.

Computational Characterization of the Reactivity of Compound I in Unspecific Peroxygenases.

Unspecific peroxygenases (UPOs) are emerging as promising biocatalysts for selective oxyfunctionalization of unactivated C-H bonds. However, their potential in large-scale synthesis is currently constrained by suboptimal chemical selectivity. Improving the selectivity of UPOs requires a deep understanding of the molecular basis of their catalysis.

A high mass loading flexible electrode with a sheet-like MnO/NiMoO@NiCo LDH on a carbon cloth for supercapacitors.

Mass loading is an important parameter to evaluate the application potential of active materials in high-capacity supercapacitors. Synthesizing active materials with high mass loading is a promising strategy to improve high performance energy storage devices. Preparing electrode materials with a porous structure is of significance to overcome the disadvantages brought by high mass loading.

Understanding the Multifaceted Mechanism of Compound I Formation in Unspecific Peroxygenases through Multiscale Simulations.

Unspecific peroxygenases (UPOs) can selectively oxyfunctionalize unactivated hydrocarbons by using peroxides under mild conditions. They circumvent the oxygen dilemma faced by cytochrome P450s and exhibit greater stability than the latter. As such, they hold great potential for industrial applications.

Mobile barrier mechanisms for Na-coupled symport in an MFS sugar transporter.

While many 3D structures of cation-coupled transporters have been determined, the mechanistic details governing the obligatory coupling and functional regulations still remain elusive. The bacterial melibiose transporter (MelB) is a prototype of the Na-coupled major facilitator superfamily transporters. With a conformational nanobody (Nb), we determined a low-sugar affinity inward-facing Na-bound cryoEM structure.

On the Simulation of Thermal Isomerization of Molecular Photoswitches in Biological Systems.

Molecular photoswitches offer precise, reversible photocontrol over biomolecular functions and are promising light-regulated drug candidates with minimal side effects. Quantifying thermal isomerization rates of photoswitches in their target biomolecules is essential for fine-tuning their light-controlled drug activity. However, the effects of protein binding on isomerization kinetics remain poorly understood, and simulations are crucial for filling this gap.

Prolonged persistence of canine distemper virus RNA, and virus isolation in naturally infected shelter dogs.

Canine distemper virus remains an important source of morbidity and mortality in animal shelters. RT-PCR is commonly used to aid diagnosis and has been used to monitor dogs testing positive over time to gauge the end of infectious potential. Many dogs excrete viral RNA for prolonged periods which has complicated disease management.

Multiscale simulation unravels the light-regulated reversible inhibition of dihydrofolate reductase by phototrexate.

Molecular photoswitches are widely used in photopharmacology, where the biomolecular functions are photo-controlled reversibly with high spatiotemporal precision. Despite the success of this field, it remains elusive how the protein environment modulates the photochemical properties of photoswitches. Understanding this fundamental question is critical for designing more effective light-regulated drugs with mitigated side effects.

Molecular Basis for the Cation Selectivity of Salmonella typhimurium Melibiose Permease.

Cation selectivity and coupling are important attributes of cation-coupled symporters. Salmonella typhimurium melibiose permease (MelB) catalyzes the co-transport of galactosides with cations (H, Li, or Na). 3-D crystal structures of MelB have revealed the molecular recognition for sugar substrates, but the cation binding and coupling mechanisms have not been defined to atomic levels.

High-performance quasi-solid-state flexible supercapacitors based on a flower-like NiCo metal-organic framework.

NiCo metal-organic framework (MOF) electrodes were prepared by a simple hydrothermal method. The flower-like NiCo MOF electrode exhibited an exciting potential window of 1.2 V and an excellent specific capacitance of 927.

Effects of Enzyme-Ligand Interactions on the Photoisomerization of a Light-Regulated Chemotherapeutic Drug.

Molecular photoswitches permit using light to control protein activity with high spatiotemporal resolutions, thereby alleviating the side effects of conventional chemotherapy. However, due to the challenges in probing ultrafast photoisomerization reactions in biological environments, it remains elusive how the protein influences the photochemistry of the photoswitches, which hampers the rational design of light-regulated therapeutics. To overcome this challenge, we employed first-principles nonadiabatic dynamics simulations to characterize the photodynamics of the phototrexate (PTX), a recently developed photoswitchable anticancer chemotherapeutic that reversibly inhibits its target enzyme dihydrofolate reductase (DHFR).

Protein confinement fine-tunes aggregation-induced emission in human serum albumin.

Luminogens exhibiting aggregation-induced-emission characteristics (AIEgens) have been designed as sensitive biosensors thanks to their "turn-on" fluorescence upon target binding. However, their AIE mechanism in biomolecules remains elusive except for the qualitative picture of restricted intramolecular motions. In this work, we employed simulations to investigate the AIE mechanism of two tetraphenylethylene derivatives recently developed for sensitive detection of human serum albumin (HSA) in biological fluids.

Transition Metal Oxide Electrode Materials for Supercapacitors: A Review of Recent Developments.

In the past decades, the energy consumption of nonrenewable fossil fuels has been increasing, which severely threatens human life. Thus, it is very urgent to develop renewable and reliable energy storage devices with features of environmental harmlessness and low cost. High power density, excellent cycle stability, and a fast charge/discharge process make supercapacitors a promising energy device.

First-Principles Nonadiabatic Dynamics Simulation of Azobenzene Photodynamics in Solutions.

The photoisomerization of azobenzene is a prototypical reaction of various light-activated processes in material and biomedical sciences. However, its reaction mechanism has been under debate for decades, partly due to the challenges in computational simulations to accurately describe the molecule's photodynamics. A recent study (.

Electrostatic Control of Photoisomerization in Channelrhodopsin 2.

Channelrhodopsin 2 (ChR2) is the most commonly used tool in optogenetics. Because of its faster photocycle compared to wild-type (WT) ChR2, the E123T mutant of ChR2 is a useful optogenetic tool when fast neuronal stimulation is needed. Interestingly, in spite of its faster photocycle, the initial step of the photocycle in E123T (photoisomerization of retinal protonated Schiff base or RPSB) was found experimentally to be much slower than that of WT ChR2.

Parallel molecular mechanisms for enzyme temperature adaptation.

The mechanisms that underly the adaptation of enzyme activities and stabilities to temperature are fundamental to our understanding of molecular evolution and how enzymes work. Here, we investigate the molecular and evolutionary mechanisms of enzyme temperature adaption, combining deep mechanistic studies with comprehensive sequence analyses of thousands of enzymes. We show that temperature adaptation in ketosteroid isomerase (KSI) arises primarily from one residue change with limited, local epistasis, and we establish the underlying physical mechanisms.

Nonadiabatic Dynamics Simulation of the Wavelength-Dependent Photochemistry of Azobenzene Excited to the nπ* and ππ* Excited States.

Azobenzene is one of the most ubiquitous photoswitches in photochemistry and a prototypical model for photoisomerizing systems. Despite this, its wavelength-dependent photochemistry has puzzled researchers for decades. Upon excitation to the higher energy ππ* excited state instead of the dipole-forbidden nπ* state, the quantum yield of isomerization from - to -azobenzene is halved.

First-Principles Characterization of the Elusive I Fluorescent State and the Structural Evolution of Retinal Protonated Schiff Base in Bacteriorhodopsin.

The conversion of light energy into work is essential to life on earth. Bacteriorhodopsin (bR), a light-activated proton pump in , has served for many years as a model system for the study of this process in photoactive proteins. Upon absorption of a photon, its chromophore, the retinal protonated Schiff base (RPSB), isomerizes from its native all- form to a 13- form and pumps a proton out of the cell in a process that is coupled to eventual ATP synthesis.

Proton-Induced Conformational and Hydration Dynamics in the Influenza A M2 Channel.

The influenza A M2 protein is an acid-activated proton channel responsible for acidification of the inside of the virus, a critical step in the viral life cycle. This channel has four central histidine residues that form an acid-activated gate, binding protons from the outside until an activated state allows proton transport to the inside. While previous work has focused on proton transport through the channel, the structural and dynamic changes that accompany proton flux and enable activation have yet to be resolved.