Design Two Novel Tetrahydroquinoline Derivatives against Anticancer Target LSD1 with 3D-QSAR Model and Molecular Simulation.

Lysine-specific demethylase 1 (LSD1) is a histone-modifying enzyme, which is a significant target for anticancer drug research. In this work, 40 reported tetrahydroquinoline-derivative inhibitors targeting LSD1 were studied to establish the three-dimensional quantitative structure-activity relationship (3D-QSAR). The established models CoMFA (Comparative Molecular Field Analysis (q2 = 0.778, Rpred2 = 0.709)) and CoMSIA (Comparative Molecular Similarity Index Analysis (q2 = 0.764, Rpred2 = 0.713)) yielded good statistical and predictive properties. Based on the corresponding contour maps, seven novel tetrahydroquinoline derivatives were designed. For more information, three of the compounds (D1, D4, and Z17) and the template molecule 18x were explored with molecular dynamics simulations, binding free energy calculations by MM/PBSA method as well as the ADME (absorption, distribution, metabolism, and excretion) prediction. The results suggested that D1, D4, and Z17 performed better than template molecule 18x due to the introduction of the amino and hydrophobic groups, especially for the D1 and D4, which will provide guidance for the design of LSD1 inhibitors.

Toxic Effect of Fullerene and Its Derivatives upon the Transmembrane ß2-Adrenergic Receptors.

Numerous experiments have revealed that fullerene (C60) and its derivatives can bind to proteins and affect their biological functions. In this study, we explored the interaction between fullerine and the ß2-adrenergic receptor (ß2AR). The MD simulation results show that fullerene binds with the extracellular loop 2 (ECL2) and intracellular loop 2 (ICL2) of ß2AR through hydrophobic interactions and π-π stacking interactions. In the C60_in1 trajectory, due to the π-π stacking interactions of fullerene molecules with PHE and PRO residues on ICL2, ICL2 completely flipped towards the fullerene direction and the fullerene moved slowly into the lipid membrane. When five fullerene molecules were placed on the extracellular side, they preferred to stack into a stable fullerene cluster (a deformed tetrahedral aggregate), and had almost no effect on the structure of ß2AR. The hydroxyl groups of fullerene derivatives (C60(OH)X, X represents the number of hydroxyl groups, X = 4, 8) can form strong hydrogen bonds with the ECL2, helix6, and helix7 of ß2AR. The hydroxyl groups firmly grasp the ß2AR receptor like several claws, blocking the binding entry of ligands. The simulation results show that fullerene and fullerene derivatives may have a significant effect on the local structure of ß2AR, especially the distortion of helix4, but bring about no great changes within the overall structure. It was found that C60 did not compete with ligands for binding sites, but blocked the ligands' entry into the pocket channel. All the above observations suggest that fullerene and its derivatives exhibit certain cytotoxicity.

Ultra-coarse-graining modeling of liquid water.

It is a great challenge to develop ultra-coarse-grained models in simulations of biological macromolecules. In this study, the original coarse-graining strategy proposed in our previous work [M. Li and J. Z. H. Zhang, Phys. Chem. Chem. Phys. 23, 8926 (2021)] is first extended to the ultra-coarse-graining (UCG) modeling of liquid water, with the NC increasing from 4-10 to 20-500. The UCG force field is parameterized by the top-down strategy and subsequently refined on important properties of liquid water by the trial-and-error scheme. The optimal cutoffs for non-bonded interactions in the NC = 20/100/500 UCG simulations are, respectively, determined on energy convergence. The results show that the average density at 300 K can be accurately reproduced from the well-refined UCG models while it is largely different in describing compressibility, self-diffusion coefficient, etc. The density-temperature relationships predicted by these UCG models are in good agreement with the experiment result. Besides, two polarizable states of the UCG molecules are observed after simulated systems are equilibrated. The ion-water RDFs from the ion-involved NC = 100 UCG simulation are nearly in accord with the scaled AA ones. Furthermore, the concentration of ions can influence the ratio of two polarizable states in the NC = 100 simulation. Finally, it is illustrated that the proposed UCG models can accelerate liquid water simulation by 114-135 times, compared with the TIP3P force field. The proposed UCG force field is simple, generic, and transferable, potentially providing valuable information for UCG simulations of large biomolecules.

A three-point coarse-grained model of five-water cluster with permanent dipoles and quadrupoles.

As coarse-grained (CG) studies of large biomolecules increase, developments of reliable CG solvent models become particularly important. In this work, we reduce five water molecules into a three-point CG model with permanent dipole and quadrupole moments. In the CG force field, the modified Morse potential is utilized and an ideal three-water cluster is designed to derive CG-level permanent multipoles. The new CG model is parametrized on the AMOEBA polarizable force field. Various important properties of liquid water are examined to validate the new CG model. Results show that the new CG model can correctly reproduce certain important experimental properties such as density, isothermal compressibility and relative static dielectric permittivity, even better than the existing AA models. Additionally, the CPU tests reveal that the CG model can accelerate molecular dynamics simulations by a factor of 19 compared to the popular AA force field. Compared with the fix-point-charge model widely used in other CG models, the permanent-multipole-based CG model describes more rigid electrostatic attractions. This study also illustrates that the permanent multipole moments contribute a lot to the electrostatic calculations in CG simulation.

Double-Well Ultra-Coarse-Grained Model to Describe Protein Conformational Transitions.

The double-well model is usually used to describe the conformational transition between two states of a protein. Since conformational changes usually occur within a relatively large time scale, coarse-grained models are often used to accelerate the dynamic process due to their inexpensive computational cost. In this work, we develop a double-well ultra-coarse-grained (DW-UCG) model to describe the conformational transitions of the adenylate kinase, glutamine-binding protein, and lactoferrin. The coarse-grained simulation results show that the DW-UCG model of adenylate kinase captures the crucial intermediate states in the LID-closing and NMP-closing pathways, reflecting the key secondary structural changes in the conformational transition. A comparison of the different DW-UCG models of adenylate kinase indicates that an appropriate choice of bead resolution could generate the free energy landscape that is comparable to that from the residue-based model. The coarse-grained simulations for the glutamine-binding protein and lactoferrin also demonstrate that the DW-UCG model is valid in reproducing the correct two-state behavior for their functional study, which indicates the potential application of the DW-UCG model in investigating the mechanism of conformational changes of large proteins.

How CuCl and CuCl2 Insert into C-N Bonds of Diazo Compounds: An Electronic Structure and Mechanistic Study.

The transition-metal Cu catalysts CuCl and CuCl2 have been widely employed to catalyze a series of chemical reactions with diazo compounds because of their high efficiency and selectivity. However, how to yield the active Cu carbene species from the Cu catalysts and diazo compounds still remains unclear. In this work, we performed a comprehensive theoretical investigation on the electronic structures of CuCl and CuCl2 in solution. The results indicate that the most stable structures for CuCl and CuCl2 are dimer and monomer, respectively. The C-N bond insertion of aryldiazoacetate by CuCl yields a stable bimetallic carbene species, which differs from the monometallic carbene generated from CuCl2.

Atomic-level reconstruction of biomolecules by a rigid-fragment- and local-frame-based (RF-LF) strategy.

Coarse-grained (CG) model has been a powerful tool in bridging the gap between theoretical studies and experimental phenomena in biological computing field. The reconstruction from a CG model to an atomic-detail structure is especially important in CG studies of biological systems. In this work, a rigid-fragment- and local-frame-based (RF-LF) backmapping method was proposed to achieve reverse mapping from CG models to atomic-level structures. The initial atomic-level structures were further refined to yield the final backmapping ones. With the popular Martini force field, the performance of the RF-LF method was extensively examined in the CG → AA (CG to AA) backmapping of protein/DNA/RNA systems. Besides, the RF-LF method was also extended to the backmapping of the TMFF model. Numerical results illustrate that the RF-LF backmapping method is generic and parameter-free and can provide a promising way to tackle atomic-level studies in CG models.

Determining Optimal Coarse-Grained Representation for Biomolecules Using Internal Cluster Validation Indexes.

The development of ultracoarse-grained models for large biomolecules needs to derive the optimal number of coarse-grained (CG) sites to represent the targets. In this work, we propose to use the statistical internal cluster validation indexes to determine the optimal number of CG sites that are optimized based on the essential dynamics coarse-graining method. The calculated curves of Calinski-Harabasz and Silhouette Coefficient indexes exhibit the extrema corresponding to the similar CG numbers. The calculated ratios of the optimal CG numbers to the residue numbers of fine-grained models are in the range from 4 to 2. The comparison of the stability of index results indicates that Calinski-Harabasz index is the better choice to determine the optimal CG representation in coarse-graining. © 2019 Wiley Periodicals, Inc.

Origins of Protons in C-H Bond Insertion Products of Phenols: Proton-Self-Sufficient Function via Water Molecules.

Water molecules can serve as proton shuttles for proton transfer in the C-H bond insertion reactions catalyzed by transition metal complexes. Recently, the control experiments performed for C-H bond insertion of phenol and anisol by gold carbenes show that large discrepancy exists in the yields of hydrogenated and deuterated products. Thus, we conducted a detailed theoretical analysis on the function of water molecules in the C-H bond insertion reactions. The comparison of calculated results and control experiments indicates that the solution water molecules play a crucial role of proton shuttle in C-H bond insertion. In particular, it was found that the hydroxyl groups in phenols were capable of donating protons via water shuttles for the production of C-H products, which had a substantial influence on the yields of inserted products. The hydroxyl groups instead of C-H bonds in phenols function like "proton reservoirs" in the C-H bond insertion, which we call the "proton self-sufficient" (PSS) function of phenol. The PSS function of phenol indicates that the substrates with and without proton reservoirs will lead to different C-H bond insertion products.

Performance Comparison of Systematic Methods for Rigorous Definition of Coarse-Grained Sites of Large Biomolecules.

Construction of coarse-grained (CG) models for large biomolecules used for multiscale simulations demands a rigorous definition of CG sites for them. Several coarse-graining methods such as the simulated annealing and steepest descent (SASD) based on the essential dynamics coarse-graining (ED-CG) or the stepwise local iterative optimization (SLIO) based on the fluctuation maximization coarse-graining (FM-CG), were developed to do it. However, the practical applications of these methods such as SASD based on ED-CG are subject to limitations because they are too expensive. In this work, we extend the applicability of ED-CG by combining it with the SLIO algorithm. A comprehensive comparison of optimized results and accuracy of various algorithms based on ED-CG show that SLIO is the fastest as well as the most accurate algorithm among them. ED-CG combined with SLIO could give converged results as the number of CG sites increases, which demonstrates that it is another efficient method for coarse-graining large biomolecules. The construction of CG sites for Ras protein by using MD fluctuations demonstrates that the CG sites derived from FM-CG can reflect the fluctuation properties of secondary structures in Ras accurately.

DFT Calculations on the Mechanism of Transition-Metal-Catalyzed Reaction of Diazo Compounds with Phenols: O-H Insertion versus C-H Insertion.

The reaction of diazo compounds with transition-metal carbenes is an efficient way to achieve the functionalization of chemical bonds in organic molecules, especially for the C-H and O-H bonds. However, the selective mechanisms of C-H and O-H bond insertions by various metal carbenes such as Rh and Cu complexes are not quite clear. In this work, we performed a comprehensively theoretical investigation of the phenol C-H and O-H bonds inserted by Rh and Cu carbenes by using DFT calculations. The calculated results reveal that the nucleophilic additions of phenols to the Rh and Cu carbenes in the C-H bond insertions are the rate-determining steps of whole reactions, which are higher than the barriers in the O-H insertions. In the process of intramolecular [1,3]-H transfer, the Rh and Cu ligands in their carbenes tend to dissociate into solution rather than the intramolecular migration due to their weak metal-carbon bonds. A deeply theoretical analysis of the electronic structures of Rh, Cu, and Au carbenes as well as their complexes elucidated their differences in the chemoselectivity of C-H and O-H insertion products, which agrees with the experimental observations well.

Mechanistic Investigation of Aromatic C(sp(2))-H and Alkyl C(sp(3))-H Bond Insertion by Gold Carbenes.

It was recently reported that the gold-carbenes have an unprecedented catalysis toward the functionalization of C(sp(2))-H bonds of aromatic compounds. However, the associated mechanisms of C(sp(2))-H bonds inserted by gold-carbenes have not been comprehensively understood. We carried out a detailed mechanistic investigation of gold-carbene insertion into the C(sp(2))-H bond of anisole by means of theoretical calculations and control experiments. It significantly reveals that the aromatic C(sp(2))-H bond activation starts with the electrophilic addition of aromatic carbon toward the carbene carbon and subsequently followed the [1,3]-proton shift to form an enol intermediate. The rearrangement of enol proceeds through the mechanisms of proton transfer assisted by water molecules or enol intermediates, which are supported by our control experiments. It was also found that the C(sp(3))-H insertions of alkanes by gold-carbenes proceed through a concerted process via a three-centered transition state. The further comparison of different mechanisms provides a clear theoretical scheme to account for the difference in aromatic C(sp(2))-H and alkyl C(sp(3))-H bond activation, which is instructive for the further experimental functionalization of C-H bonds by gold-carbenes.

Constructing Optimal Coarse-Grained Sites of Huge Biomolecules by Fluctuation Maximization.

Coarse-grained (CG) models are valuable tools for the study of functions of large biomolecules on large length and time scales. The definition of CG representations for huge biomolecules is always a formidable challenge. In this work, we propose a new method called fluctuation maximization coarse-graining (FM-CG) to construct the CG sites of biomolecules. The defined residual in FM-CG converges to a maximal value as the number of CG sites increases, allowing an optimal CG model to be rigorously defined on the basis of the maximum. More importantly, we developed a robust algorithm called stepwise local iterative optimization (SLIO) to accelerate the process of coarse-graining large biomolecules. By means of the efficient SLIO algorithm, the computational cost of coarse-graining large biomolecules is reduced to within the time scale of seconds, which is far lower than that of conventional simulated annealing. The coarse-graining of two huge systems, chaperonin GroEL and lengsin, indicates that our new methods can coarse-grain huge biomolecular systems with up to 10,000 residues within the time scale of minutes. The further parametrization of CG sites derived from FM-CG allows us to construct the corresponding CG models for studies of the functions of huge biomolecular systems.

Origins of unique gold-catalysed chemo- and site-selective C-H functionalization of phenols with diazo compounds.

In past decade, gold revealed more and more unique properties in carbene chemistry. It was disclosed in our recent communication (J. Am. Chem. Soc. 2014, 136, 6904) that gold carbenes have unprecedented chemo- and site-selectivity and ligand effect toward the functionalization of C-H bonds in phenols. In this full article, we report a comprehensively combined theoretical and experimental study on the mechanism of the insertion of gold carbenes into C-H and O-H bonds in phenol. It significantly revealed that the ligands have an important effect on C-H insertion and the reaction proceeds through a pathway involving the formation of an enolate-like intermediate. Moreover, two water molecules serving as a proton shuttle are believed to be the key issue for achieving chemoselective C-H functionalization, which is strongly supported by the DFT calculations and control experiments. It is the first time that a clear explanation is given about the prominent catalysis of gold carbenes toward C-H functionalization based on a theoretical and experimental study.