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Inhibition of the Embryonic Ectoderm Development (EED) subunit in Polycomb Repressive Complex 2 (PRC2) can inhibit tumor growth. In this paper, we selected six experimentally designed EED competitive Inhibitors of the triazolopyrimidine derivatives class. We investigated the difference in the binding mode of the natural substrate to the Inhibitors and the effects of differences in the parent nuclei, heads, and tails of the Inhibitors on the inhibitory capacity. The results showed that the binding free energy of this class of Inhibitors was close to or lower compared to the natural substrate, providing an energetic basis for competitive inhibition. For the Inhibitors, the presence of a strong negatively charged group at the 6-position of the parent nucleus or the 8′-position of the head would make the hydrogen atom on the head imino group prone to flip, resulting in the vertical movement of the parent nucleus, which significantly decreased the inhibitory ability. When the 6-position of the parent nucleus was a nonpolar group, the parent nucleus would move horizontally, slightly decreasing the inhibitory ability. When the 8′-position of the head was methylene, it formed an intramolecular hydrophobic interaction with the benzene ring on the tail, resulting in a significant increase in inhibition ability. [ABSTRACT FROM AUTHOR]

E. coli thioesterase 'TesA is an important enzyme in fatty acid production. Medium-chain fatty acids (MCFAs, C6-C10) are of great interest due to their similar physicochemical properties to petroleum-based oleo-chemicals. It has been shown that wild-type 'TesA had better selectivity for long-chain acyl substrates (≥C16), while the two mutants 'TesAE142D/Y145G and 'TesAM141L/E142D/Y145G had better selectivity for medium-chain acyl substrates. However, it is difficult to obtain the selectivity mechanism of substrates for proteins by traditional experimental methods. In this study, in order to obtain more MCFAs, we analyzed the binding mode of proteins ('TesA, 'TesAE142D/Y145G and 'TesAM141L/E142D/Y145G) and substrates (C16/C8-N-acetylcysteamine analogs, C16/C8-SNAC), the key residues and catalytic mechanisms through molecular docking, molecular dynamics simulations and the molecular mechanics Poisson–Boltzmann surface area (MM/PBSA). The results showed that several main residues related to catalysis, including Ser10, Asn73 and His157, had a strong hydrogen bond interaction with the substrates. The mutant region (Met141-Tyr146) and loop107–113 were mainly dominated by Van der Waals contributions to the substrates. For C16-SNAC, except for 'TesAM141L/E142D/Y145G with large conformational changes, there were strong interactions at both head and tail ends that distorted the substrate into a more favorable high-energy conformation for the catalytic reaction. For C8-SNAC, the head and tail found it difficult to bind to the enzyme at the same time due to insufficient chain length, which made the substrate binding sites more variable, so 'TesAM141L/E142D/Y145G with better binding sites had the strongest activity, and 'TesA had the weakest activity, conversely. In short, the matching substrate chain and binding pocket length are the key factors affecting selectivity. This will be helpful for the further improvement of thioesterases. [ABSTRACT FROM AUTHOR]

Adhesion G-protein-coupled receptors (aGPCRs)—a major family of GPCRs—play critical roles in the regulation of tissue development and cancer progression. The orphan receptor GPR97, activated by glucocorticoid stress hormones, is a prototypical aGPCR. Although it has been established that the palmitoylation of the C-terminal Go protein is essential for Go's efficient engagement with the active GPR97, the detailed allosteric mechanism remains to be clarified. Hence, we performed extensive large-scale molecular dynamics (MD) simulations of the GPR97−Go complex in the presence or absence of Go palmitoylation. The conformational landscapes analyzed by Markov state models revealed that the overall conformation of GPR97 is preferred to be fully active when interacting with palmitoylated Go protein. Structural and energetic analyses indicated that the palmitoylation of Go can allosterically stabilize the critical residues in the ligand-binding pocket of GPR97 and increase the affinity of the ligand for GPR97. Furthermore, the community network analysis suggests that the palmitoylation of Go not only allosterically strengthens the internal interactions between Gαo and Gβγ, but also enhances the coupling between Go and GPR97. Our study provides mechanistic insights into the regulation of aGPCRs via post-translational modifications of the Go protein, and offers guidance for future drug design of aGPCRs. [ABSTRACT FROM AUTHOR]

The 2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL-20) is considered as the most promising energetic materials (EMs) in terms of its detonation performance. Nonetheless, its applications are limited due to high sensitivity and low phase stability. Thermal decomposition behavior especially for the initial reaction pathway determines its reactivity and sensitivity. An in-depth discernment of the innate decomposition pathways of CL-20 would facilitate the precision tailoring and augmentation of its performance. The thermal behavior and decomposition mechanisms of CL-20 are largely dependent on the experimental conditions and chemical environments. In this brief review, the effects of those factors on the thermal decomposition mechanisms of CL-20 are summarized from both theoretical and experimental perspectives. In particular, the interaction mechanisms between CL-20 and the other commonly used energetic compounds are simultaneously elucidated. • Environmental conditions and contact materials influence the thermal decomposition mechanism of CL-20. • High temperatures can weaken the influence of physical factors on the decomposition of CL-20. • The influence of contact materials on the decomposition mechanism of CL-20 varies depending on the material used. • Need to strengthen theoretical research on the decomposition mechanism of CL-20 under chemical environments. [ABSTRACT FROM AUTHOR]

• PVAc could be dissolved in CO 2 when the pressure was much higher than 30 MPa. • Cosolvents could decrease the transition points of PVAc in CO 2. • The mixtures of CO 2 and cosolvents have the solubility parameters close to PVAc. • The LA-LB interactions are the main influence factor of PVAc dissolving in CO 2. • The generated new interactions by cosolvents have great influence. The dissolution behavior of polymers in CO 2 has become increasingly important to the applications of CO 2 in industry. Experimental results showed that PVAc could be dissolved in CO 2 at a high pressure. When cosolvents such as ethanol, acetic acid, and ethyl acetate were present in the system, the transition points could be decreased with the increase in cosolvent concentration. In this work, the influence mechanisms of cosolvents on dissolution behaviors of PVAc in supercritical CO 2 were investigated by molecular dynamics simulation methods. First, the cohesive energy and solubility parameters of PVAc, cosolvents and CO 2 were analyzed. Compared with CO 2 , the mixtures of CO 2 and cosolvents have closer solubility parameters with PVAc to enhance the dissolubility of PVAc within them. Moreover, the mechanism of PVAc dissolution in CO 2 and the effects of cosolvents on decreasing the transition points were investigated. The Lewis acid–Lewis base (LA-LB) interactions between O atoms in PVAc and C atoms in CO 2 are the main influencing factors of PVAc dissolution in CO 2. The presence of cosolvent can generate new interactions, such as hydrogen bonding and LA-LB interactions, which have different influences on the LA-LB interactions between PVAc and CO 2. Ethanol and ethyl acetate have no great influence on these LA-LB interactions, while acetic acid exerts considerable influence. [ABSTRACT FROM AUTHOR]

• Aqueous nano-film evaporation is studied by molecular dynamics simulation. • The external electric field on the evaporation of the aqueous nano-film is focused in this work. • Aqueous film evaporation was enhanced using a high electric field parallel to the surface of aqueous film. In this work, molecular dynamics simulation has been applied to investigate the influence of external electric field on the evaporation of the aqueous nano-film. The evaporation of the aqueous nano-film with 2240 water molecules and 50 NaCl on a gold (1 0 0) surface is analyzed at the electric fields with various intensities (0, 0.05, 0.1, 0.2 and 0.3 V nm−1) and directions. The predictions show that the evaporation of aqueous film is remarkably enhanced when the electric field E x = 0.2 or 0.3 V nm−1 is parallel to the aqueous film surface. It is also noted that free ions in the aqueous film are accelerated under the action of the higher E x and water molecules in the hydration shell move together with the ions due to the hydration effect. As a result, the interaction between water molecules decreases, which is responsible for increasing the evaporation of the aqueous film under the action of the higher E x. While applying the electric field E y = ±0.3 V nm−1 perpendicular to the aqueous film, ions cannot be in accelerated motion due to the existence of a solid-liquid interface and a liquid-gas surface in y -direction. Therefore, the evaporation enhancement is much lower than that of the aqueous film under the action of the E x. [ABSTRACT FROM AUTHOR]

• The deformation path depends strongly on the uniaxial tensile directions. • An intermediated phase (BCC) was firstly found during the HCP → FCC transformation in titanium. • A new formation path of { 10 1 - 1 } twinning relation through BCC stage was observed in titanium. • The pure-shuffle nucleation mechanism of { 10 1 - 2 } twin was found in titanium. In this work, effects of uniaxial tensile directions on the deformation mechanisms of a hexagonal close-packed (HCP) titanium crystalline were investigated by molecular dynamics simulations. Three uniaxial tensile directions, namely the [ 2 1 - 1 - 0 ], [ 01 1 - 0 ] and [ 0001 ] directions, were studied. When the tensile loading was along the [ 2 1 - 1 - 0 ] direction, the parent HCP phase transformed firstly into the body-centered cubic (BCC) phase following the Pitsch-Schrader orientation relationship (OR), and then transformed either into the face-centered cubic (FCC) phase following the Bain path or back to the HCP phase following different variants of the Pitsch-Schrader OR. The new-forming and matrix HCP structures were in a { 10 1 - 1 } twinning relationship with each other. The newly formed FCC phase was in a prismatic-type (P-type) OR with the HCP matrix and in a basal-type (B-type) relationship with the new-forming HCP structure at individual contacting interface. The FCC/HCP interfaces in the P-type OR was immobile while that in the B-type OR propagated by the slip of Shockley partial dislocations. Both FCC/HCP interfaces in the P-type and B-type ORs were observed under high-resolution transmission electron microscope. With the tensile loading along the [ 01 1 - 0 ] direction, deformation mechanism of the system was dominated by the slip and dissociation of prismatic dislocations. The system stretched along the [ 0001 ] direction deformed mainly through the slip and dissociation of pyramidal dislocations, as well as through the activation of { 10 1 - 2 } twinning by a pure shuffle mechanism. The present investigation can provide clues in designing titanium alloys with both high strength and good plasticity. [ABSTRACT FROM AUTHOR]

• Evaporation enhancement of nano-films is larger at the alternating electric field. • Interaction among water molecules becomes weaker at the alternating electric field. • Evaporation is more significant for the electric field parallel to the film surface. In this work, molecular dynamics simulation has been adopted to investigate the influence of square-wave alternating electric field on the evaporation of pure water and aqueous nano-films. The evaporation of the films with 3360 water molecules and 0, 1.11 and 2.18 mol L−1 NaCl on a hot gold (1 0 0) surface was analyzed. The results showed that both the evaporation of water and aqueous films were enhanced by applying the alternating electric field. Compared with the liquid films at the absence of the electric field, the maximum evaporation rates increased 1.71, 1.70 and 1.66 times for water film and aqueous films with 1.11 and 2.18 mol L−1 NaCl for the frequency of 500 GHz, respectively. The reasons were inferred that the water film subjected to the time-varying electrical force resulted in increasing of the rotational and translational kinetic energy of water molecules. Thus applying the alternating electric field accelerated the temperature rise of the water film and enhanced thermal volume expansion of the water film. In addition, the interaction between water molecules became weaker and the water molecules escaped from the water film more easily. The MD simulation also showed that the evaporation enhancement was more significant for the alternating electric field parallel to the films surface than in the perpendicular direction. [ABSTRACT FROM AUTHOR]

The overexpression of p21-activated kinase 4 (PAK4) is associated with a variety of cancers. In this paper, the binding modes and inhibitory mechanisms of four 7H-pyrrolo[2,3-d]pyrimidine competitive inhibitors of PAK4 were investigated at the molecular level, mainly using molecular dynamics simulations and binding free energy calculations. The results show that the inhibitors had strong interactions with the hinge region, the β-sheets, and the residues with charged side chains around the 4-substituent. The terminal amino group of the inhibitor 5n was different from the other three, which could cause the enhancement of hydrogen bonds or electrostatic interactions formed with the surrounding residues. Thus, inhibitor 5n had the strongest inhibition capacity. The different halogen atoms on the 2-substituents of the inhibitors 5h, 5g, and 5e caused differences in the positions of the 2-benzene rings and affected the interactions of the hinge region. It also affected to some extent the orientations of the 4-imino groups and consequently their affinities for the surrounding charged residues. The combined results lead to the weakest inhibitory capacity of inhibitor 5e. [ABSTRACT FROM AUTHOR]

[Display omitted] • It shows a strong interaction between SCMC and metal surfaces according to the adsorption configuration and binding energy. • The SCMC gets close to the different metal surfaces in water environment as well as the anhydrous conditions. • The interaction energy decreases from SCMC and the metal surfaces compared to no water environment. • The adsorption energy between SCMC and the metal surfaces increases with the increasing polymerization degree of SCMC. Sodium carboxymethyl cellulose (SCMC) is an effective corrosion inhibitor that provides good protection to metal surfaces. This study investigates the corrosion inhibition properties of SCMC on Fe, Cu, and Al using molecular dynamics simulations. The effects of the adsorption configuration, interaction energy of SCMC on different metal surfaces, and the degree of polymerization change of SCMC molecules were analyzed. The results show that under anhydrous conditions, the adsorption energy between the SCMC and the metal surface increases with its degree of polymerization. The SCMC also gets close to the different metal surfaces, and the carboxyl oxygen atoms in the molecular chain of SCMC are mainly distributed at a distance of about 2.9 Å from the metal surface. It illustrates a strong interaction between SCMC and metal surfaces, and the SCMC breaks free from the water molecules and eventually still adsorbs to the metal surface in water environment, but the adsorption energy is reduced by the water environment. [ABSTRACT FROM AUTHOR]

• With the increase of grafting ratio, the solubility parameter of carbon nanotubes (SWCNTs) first decrease, reach a minimum and then increase. • The SWCNTs with different functional groups exhibit different compatibility behaviors with styrene butadiene rubber (SBR). • Each functional group has the optimum grafting ratio at which the compatibility is the best. From the perspective of thermodynamics, the compatibility between filler and matrix determines the dispersion and morphology of filler and further determines the final properties of composites. At present, it is difficult to obtain a quantitative relationship between the surface chemistry of filler and compatibility with matrix through experimental means. In this study, the quantitative relationship between functional groups and Hildebrand (δ T) and two-component solubility parameters (δ vdW , δ ele) of single-walled carbon nanotubes (SWCNTs) was obtained by molecular dynamics (MD) simulation. The most notable conclusion is that with the increase of grafting ratio, the δ T and δ vdW of SWCNTs first decrease, reach a minimum and then increase. This regularity makes the SWCNTs with different functional groups exhibit different compatibility behaviors with styrene butadiene rubber (SBR), resulting in different functionalization principles for different groups. Two-component solubility parameters of SWCNTs and SBR were further proved to be able to predict well their compatibility by Flory-Huggins model. Each functional group has the optimum grafting ratio at which the compatibility is the best. Additionally, the –CH 3 , –CH(O)CH– and –OH functionalized systems exist the optimum temperature for the best compatibility. The multifunctional groups is superior to a single group for the compatibility. This study provides a quantitative guidance for the functionalization of SWCNTs towards the good compatibility with SBR. [ABSTRACT FROM AUTHOR]

Lung cancer is the most frequent cause of cancer-related deaths worldwide, and mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are a common cause of non-small-cell lung cancers, which is a major subtype of lung cancers. Recently, a series of 5-methylpyrimidine-pyridinone derivatives have been designed and synthesized as novel selective inhibitors of EGFR and EGFR mutants. However, the binding-based inhibition mechanism has not yet been determined. In this study, we carried out molecular dynamic simulations and free-energy calculations for EGFR derivatives to fill this gap. Based on the investigation, the three factors that influence the inhibitory effect of inhibitors are as follows: (1) The substitution site of the Cl atom is the main factor influencing the activity through steric effect; (2) The secondary factors are repulsion between the F atom (present in the inhibitor) and Glu762, and the blocking effect of Lys745 on the phenyl ring of the inhibitor. (3) The two factors function synergistically to influence the inhibitory capacity of the inhibitor. The theoretical results of this study can provide further insights that will aid the design of oncogenic EGFR inhibitors with high selectivity. [ABSTRACT FROM AUTHOR]