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Experimental protein energy maps in the (φ, ψ) space for the dipeptides of 20 naturally occurring amino acids using the current collections of high-resolution entries in the protein data bank (PDB) are presented here. Data sets were generated for hydrogen bond distance cut-off values of 2.7 Å and 3.1 Å. Neighborhood effects of proline residues on the (φ, ψ) maps have been examined. The impact of disulphide bridges on these maps has been critically examined. The comparisons of experimental maps with those obtained using various molecular mechanics and molecular dynamics methods were published earlier. The comparison metrics are: (i) locations of global and secondary minima, (ii) percentage areas enclosed by isoenergy contours, (iii) energybased RMSD and (iv) barriers to conformational transitions. The experimental maps for individual amino acid dipeptide motifs show a higher degree of qualitative consistency with theoretical maps derived using molecular mechanics when compared to those from molecular dynamics methods. We also demonstrate that a majority of backbone conformations observed in the structures of small peptides in the Cambridge Crystallographic Database are within the allowed regions of the experimental Ramachandran maps. A few protein models obtained from NMR spectroscopy were evaluated in terms of the amino acid outlier energies using the experimental maps. [ABSTRACT FROM AUTHOR]

The cysteine and alkanethiol adsorption on Au(111) surfaces is investigated using density functional theory (DFT) and classic molecular dynamics (MD). Understanding the S–Au interaction across different scales poses major challenges. DFT provides atomic‐level precision but it hardly provides insight on nanosecond scale dynamics of this interface. Alternatively, MD, although it enables modeling larger systems for longer periods, its accuracy heavily relies on the parameterization of the force fields (FF). To address this, an MD potential is fitted using DFT calculations, bridging the gap in accuracy and efficiency. At the DFT level, it is found that PBE with DFT‐D3 reproduces complex approaches at a fraction of the computational cost. Separating PBE and DFT‐D3 contributions reveals consistent PBE energy across molecules (chemisorption), while dispersion varies (physisorption). Thus, the interaction energy of cysteine and two short‐chain alkanethiols is calculated to parameterize both Morse and Lennard–Jones (LJ) potentials. The parameterization improves the potential energy in the preferred adsorption sites: the threefold hcp and fcc with respect to the previous proposals in the literature. Furthermore, the transferability is here demonstrated. At last, these results show that LJ potentials outperform more complex Morse potentials. The procedure is general, and the codes and supporting inputs are publicly available, allowing swift generation of potential energy surfaces (PES) at the DFT level, and fitted LJ or Morse potentials to any molecular interface. [ABSTRACT FROM AUTHOR]

In this study, we introduce a comprehensive investigation into the buckling behavior of carbon nanotubes (CNTs) using a combined approach of quantum mechanics and molecular mechanics methods. A novel aspect of our research lies in the exploration of the quantum effects of fine scaling on the buckling behavior of finite‐length nanotubes across various dimensions and chiralities. Specifically, we analyze the critical buckling strain variations in CNTs with distinct lengths, diameters, and chiralities, revealing pronounced differences influenced by atomic arrangement and the type of structure used in nanotube construction. Our findings elucidate that at smaller dimensions, nn2 nanotubes exhibit a higher critical buckling strain than other chiralities, while zigzag atomic arrangements demonstrate greater resistance to torsional loading at larger diameters. Additionally, we compare the buckling behavior of nanotubes obtained by wrapping armchair and zigzag nanosheets, highlighting differential resistance trends. This research not only underscores the critical role of quantum effects in determining nanotube buckling but also provides valuable insights into the nuanced influences of atomic arrangement and nanosheet type on the mechanical properties of CNTs. Thus, our work contributes a novel perspective to the field, bridging the gap between quantum mechanics and the mechanical behavior of nanostructures, which has significant implications for the design and application of nanoscale materials [ABSTRACT FROM AUTHOR]

• The modified energy method evaluated the elastic properties of SWBNNT, and the inversion energy term was considered. • Temperature's impact on BNNT's elastic properties was explored by incorporating it as an independent variable. • MSM and continuum mechanics models are used to evaluate the changes in different bonds, bond angles, and reaction angles. The elastic properties of boron nitride nanotubes (BNNTs) were investigated utilizing an enhanced energy method. By considering small deformations and applying the principle of minimum potential energy, the variations in atomic bonds and bond angles within the nanotube structure were determined. The modified model incorporated the contribution of inversion energy to the overall potential energy of the system, leading to the derivation of analytical expressions for the Young's modulus, shear modulus, and strain energy of both armchair and zigzag BNNTs under varying temperatures. The results indicate that compared to zigzag BNNTs, the impact of inversion energy on the elastic constants of armchair BNNTs is more significant, especially at small diameters (<1 nm). In thermal environment, this study demonstrates that the change in Young's modulus of BNNTs is lower than that of carbon nanotubes (CNTs), confirming the superior thermal stability of BNNTs over CNTs. Furthermore, molecular structure mechanics (MSM) and continuum mechanics models were employed to analyze the strain energy of BNNTs. The effects of different bonds, bond angles, and inversion angles on strain energy were analyzed in a thermal environment, revealing distinct differences between the two types of BNNTs. These findings provide more accurate theoretical guidance for thermal applications based on the stretching of BNNTs. [ABSTRACT FROM AUTHOR]

In the current study, we have investigated the secondary metabolites present in ethnomedical plants used for medicinal purposes—Astilbe chinensis (EK1), Scutellaria barbata D. Don (EK2), Uncaria rhynchophylla (EK3), Fallugia paradoxa (EK4), and Curcuma zedoaria (Christm.) Thread (EK5)—and we have compared them with five compounds of synthetic origin for the inhibition of PARP-1, which is linked to abnormal DNA replication, generating carcinogenic cells. We have studied these interactions through molecular dynamics simulations of each interacting system under physiological conditions (pH, temperature, and pressure) and determined that the compounds of natural origin have a capacity to inhibit PARP-1 (Poly(ADP-ribose) Polymerase 1) in all the cases inspected in this investigation. However, it is essential to mention that their interaction energy is relatively lower compared to that of compounds of synthetic origin. Given that binding energy is mandatory for the generation of a scale or classification of which is the best interacting agent, we can say that we assume that compounds of natural origin, having a complexation affinity with PARP-1, induce cell apoptosis, a potential route for the prevention of the proliferation of carcinogenic cells.

Simple Summary: Despite considerable progress in cancer research and treatment, cancer continues to be a major health challenge, often requiring invasive treatments with substantial side effects. Immuno-therapy, which targets the immune system's PD-1/PD-L1 pathway, represents a promising alternative. This critical pathway allows cancer cells to avoid immune destruction by inhibiting T-cells. Our study employs computational techniques to develop inhibitors that block the PD-L1 pathway, specifically in the acidic environment of tumors. By analyzing around 10,000 natural compounds, we identified a potential pH-selective inhibitor that shows greater effectiveness in the acidic conditions typical of cancerous tissues. This research suggests a novel approach for experimental groups to explore, focusing on developing targeted, pH-dependent inhibitors that could mark a significant step in enhancing the precision and effectiveness of immunotherapy treatments, potentially revolutionizing cancer therapy. Immunotherapy, particularly targeting the PD-1/PD-L1 pathway, holds promise in cancer treatment by regulating the immune response and preventing cancer cells from evading immune destruction. Nonetheless, this approach poses a risk of unwanted immune system activation against healthy cells. To minimize this risk, our study proposes a strategy based on selective targeting of the PD-L1 pathway within the acidic microenvironment of tumors. We employed in silico methods, such as virtual screening, molecular mechanics, and molecular dynamics simulations, analyzing approximately 10,000 natural compounds from the MolPort database to find potential hits with the desired properties. The simulations were conducted under two pH conditions (pH = 7.4 and 5.5) to mimic the environments of healthy and cancerous cells. The compound MolPort-001-742-690 emerged as a promising pH-selective inhibitor, showing a significant affinity for PD-L1 in acidic conditions and lower toxicity compared to known inhibitors like BMS-202 and LP23. A detailed 1000 ns molecular dynamics simulation confirmed the stability of the inhibitor-PD-L1 complex under acidic conditions. This research highlights the potential of using in silico techniques to discover novel pH-selective inhibitors, which, after experimental validation, may enhance the precision and reduce the toxicity of immunotherapies, offering a transformative approach to cancer treatment. [ABSTRACT FROM AUTHOR]

A simplified molecular-dynamics-based electronic circular dichroism (ECD) approach was tested on three condensed derivatives with limited conformational flexibility and an isochroman-2H-chromene hybrid, the ECD spectra of which could not be precisely reproduced by the conventional ECD calculation protocol. Application of explicit solvent molecules at the molecular mechanics (MD) level in the dynamics simulations and subsequent TDDFT-ECD calculation for the unoptimized MD structures was able to improve the agreements between experimental and computed spectra. Since enhancements were achieved even for molecules with limited conformational flexibility, deformations caused by the solvent molecules and multitudes of conformers produced with unoptimized geometries seem to be key factors for better agreement. The MD approach could confirm that aggregation of the phenanthrene natural product luzulin A had a significant contribution to a specific wavelength range of the experimental ECD. The MD approach has proved that dimer formation occurred in solution and this was responsible for the anomalous ECD spectrum. The scope and limitations of the method have also been discussed. [ABSTRACT FROM AUTHOR]

Abstract The cysteine and alkanethiol adsorption on Au(111) surfaces is investigated using density functional theory (DFT) and classic molecular dynamics (MD). Understanding the S–Au interaction across different scales poses major challenges. DFT provides atomic‐level precision but it hardly provides insight on nanosecond scale dynamics of this interface. Alternatively, MD, although it enables modeling larger systems for longer periods, its accuracy heavily relies on the parameterization of the force fields (FF). To address this, an MD potential is fitted using DFT calculations, bridging the gap in accuracy and efficiency. At the DFT level, it is found that PBE with DFT‐D3 reproduces complex approaches at a fraction of the computational cost. Separating PBE and DFT‐D3 contributions reveals consistent PBE energy across molecules (chemisorption), while dispersion varies (physisorption). Thus, the interaction energy of cysteine and two short‐chain alkanethiols is calculated to parameterize both Morse and Lennard–Jones (LJ) potentials. The parameterization improves the potential energy in the preferred adsorption sites: the threefold hcp and fcc with respect to the previous proposals in the literature. Furthermore, the transferability is here demonstrated. At last, these results show that LJ potentials outperform more complex Morse potentials. The procedure is general, and the codes and supporting inputs are publicly available, allowing swift generation of potential energy surfaces (PES) at the DFT level, and fitted LJ or Morse potentials to any molecular interface.

Abstract In this paper, the quantum effects of fine scaling on the buckling behavior of carbon nanotubes (CNTs) under axial loading are investigated. Molecular mechanics and quantum mechanics are respectively utilized to study the buckling behavior and to obtain the molecular mechanics coefficients of fine-scale nanotubes. The results of buckling behavior of CNTs with different chiralities with finite and infinite dimensions are given, and a comparison study is presented on them. The differences between finite and infinite nanotubes reflect the quantum effects of fine scaling on the buckling behavior. In addition, the results show that the dimensional changes highly affect the mechanical properties and the buckling behavior of CNTs to certain dimensions. Moreover, dimensional changes have a significant effect on the critical buckling strain. Beside, in addition to the structure dimensions, the arrangement of structural and boundary atoms have a major influence on the buckling behavior.

The implementation of the cyclic cluster model (CCM) for molecular mechanics is presented in the framework of the computational chemistry program deMon2k. Because the CCM is particularly well-suited for the description of periodic systems with defects, it can be used for periodic QM/MM approaches where the non-periodic QM part is treated as a defect in a periodic MM surrounding. To this end, we present here the explicit formulae for the evaluation of the Ewald sum and its first- and second-order derivatives as implemented in deMon2k. The outlined implementation was tested in molecular dynamics (MD) simulations and periodic structure optimization calculations. MD simulations of an argon system were carried out using the Nosé-Hoover chain (NHC) thermostat and the Martyna-Tobias-Klein (MTK) barostat to control the temperature and pressure of the system, respectively. For the validation of CCM structure optimization a set of molecular crystals were optimized using the Ewald method for the evaluation of the electrostatic interactions. Two optimization procedures for the determination of the atomic positions and CCM cell parameters were tested. Our results show that the simultaneous optimization of the atomic positions and cell parameters is most efficient. [ABSTRACT FROM AUTHOR]

Context: Hydroxypropyl-β-cyclodextrin (HPβCD) is one of the derivatized cyclodextrins most widely used as an excipient in the pharmaceutical industry, for its capacity to improve certain drugs properties. Different configurations of HPβCD are possible depending on the number and location of the 2-hydroxypropyl groups substituted on the glucose rings. Rifampicin has become the most commonly clinically used antibiotic against tuberculosis in recent years, despite its low solubility and variable bioavailability. Different techniques and materials have been proposed to enhance the properties of rifampicin: cyclodextrin complexation is one of them. The van der Waals term was the main contribution to the interaction energy, which then decisively conditioned the complex configurations. The size of rifampicin did not allow the whole molecule to fit into the host. Moreover, interaction energy was much greater when the guest was located near each rim of HPβCD, where rifampicin was partially included in the cavity and formed inclusion complexes. The piperazine tail of rifampicin was included inside the host in minimum energy structures and the guest was situated near the primary rim of HPβCD in most cases, although the complex configurations depended on the degree of substitution. Methods: A molecular mechanics simulation based on the GROMOS 53A6 force field was applied in this work to study the inclusion complexes formed by twelve configurations of HPβCD, with different degrees of substitution and rifampicin in water solution. We determined the penetration potential, the complex structures with minimum energies, the possibility of forming inclusion complexes other than those of minimum energies and potential energy surfaces. [ABSTRACT FROM AUTHOR]

In this paper, the quantum effects of fine scaling on the buckling behavior of carbon nanotubes (CNTs) under axial loading are investigated. Molecular mechanics and quantum mechanics are respectively utilized to study the buckling behavior and to obtain the molecular mechanics coefficients of fine-scale nanotubes. The results of buckling behavior of CNTs with different chiralities with finite and infinite dimensions are given, and a comparison study is presented on them. The differences between finite and infinite nanotubes reflect the quantum effects of fine scaling on the buckling behavior. In addition, the results show that the dimensional changes highly affect the mechanical properties and the buckling behavior of CNTs to certain dimensions. Moreover, dimensional changes have a significant effect on the critical buckling strain. Beside, in addition to the structure dimensions, the arrangement of structural and boundary atoms have a major influence on the buckling behavior. [ABSTRACT FROM AUTHOR]

Prismanes have been attracting interest for nearly 50 years because of their geometric symmetry, highly strained structures, and unique applications due to their high carbon densities and bulky structures. Although [3]-, [4]-, and [5]-prismanes have been synthesised, [6]-prismanes and their derivatives remain elusive. Herein, fluorine chemistry, molecular mechanics, molecular orbital package, and density functional theory calculations were used to design and implement the photoisomerisation of octafluoro[2.2]paracyclophane (selected based on the good overlap of its lowest unoccupied molecular orbitals and short distance between the benzene rings) into octafluoro-[6]-prismane. Specifically, a dilute solution of the above precursor in CH3CN/H2O/dimethyl sulfoxide (DMSO) (2:1:8, v/v/v) solution was irradiated with ultraviolet light, with the formation of the desired product confirmed through the use of nuclear magnetic resonance spectroscopy and gas chromatography–mass spectrometry. The product was thermally stable in solution but not under work-up conditions, which complicated the further analysis and single-crystal preparation. The key criteria for successful photoisomerisation were the presence of fluorine substituents in the cyclophane structure and DMSO in the solvent system. A more stable derivative design requires the isolation of prismane products. The proposed fluorination-based synthetic strategy is applicable to developing novel high-strain molecules/materials with three-dimensional skeletons. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurological disease, and its signs and symptoms appear slowly over time. Although current Alzheimer's disease treatments can alleviate symptoms, they cannot prevent the disease from progressing. To accurately diagnose and treat Alzheimer's disease, it is therefore necessary to establish effective methods for diagnosis. Apolipoprotein E4 (ApoE4), the most frequent genetic risk factor for AD, is expressed in more than half of patients with AD, making it an attractive target for AD therapy. We used molecular docking simulations, classical molecular mechanics optimizations, and ab initio fragment molecular orbital (FMO) calculations to investigate the specific interactions between ApoE4 and the naturally occurring compounds found in the plant Moringa Oleifera. According to the FMO calculations, quercetin had the highest binding affinity to ApoE4 among the sixteen compounds because its hydroxyl groups generated strong hydrogen bonds with the ApoE4 residues Trp11, Asp12, Arg15, and Asp130. As a result, we proposed various quercetin derivatives by introducing a hydroxyl group into quercetin and studied their ApoE4 binding properties. The FMO data clearly showed that adding a hydroxyl group to quercetin improved its binding capacity to ApoE4. Furthermore, ApoE4 Trp11, Asp12, Arg15, and Asp130 residues were discovered to be required for significant interactions between ApoE4 and quercetin derivatives. They had a higher ApoE4 binding affinity than our previously proposed epicatechin derivatives. Accordingly, the current results evaluated using the ab initio FMO method will be useful for designing potent ApoE4 inhibitors that can be used as a candidate agent for AD treatment. [ABSTRACT FROM AUTHOR]

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In response to hydrostatic pressure, the cation channel transient receptor potential vanilloid 1 (TRPV1) is essential in signaling pathways linked to glaucoma. When activated, TRPV1 undergoes a gating transition from a closed to an open state that allows the influx of Ca2+ ions. However, the gating mechanism of TRPV1 in response to hydrostatic pressure at the molecular level is still lacking. To understand the effect of hydrostatic pressure on the activation of TRPV1, we conducted molecular-dynamics (MD) simulations on TRPV1 under different hydrostatic pressure configurations, with and without a cell membrane. The TRPV1 membrane-embedded model is more stable than the TPRV1-only model, indicating the importance of including the cell membrane in MD simulation. Under elevated pressure at 27.6 mmHg, we observed a more dynamic and outward motion of the TRPV1 domains in the lower-gate area than in the simulation under normal pressure at 12.6 mmHg. While a complete closed-to-open-gate transition was not evident in the limited course of our MD simulations, an increase in the channel radius at the lower gate was observed at 27.6 mmHg versus that at 12.6 mmHg. These findings provide novel information regarding the effect of hydrostatic pressure on TRPV1 channels.

Computational chemistry lets us model intermolecular interactions in ways assays cannot. My project focuses on the multi-kinase interactions of the cancer drug, imatinib. Most cancer drugs target one kinase, but some affect multiple kinases. Imatinib treats chronic myeloid leukemia by targeting ABL kinase. Proteomics data reveals it can interact with other kinases, such as KIT to treat gastrointestinal stromal tumors, but the mechanisms are unknown. Imatinib has different affinities for similar kinases, such as a 3000x difference between ABL and SRC, despite sharing 50% structural homology. Here, I investigate the conformational differences between free and imatinib-bound ABL, KIT, and SRC using Molecular Dynamics simulations to understand the key imatinib-kinase interactions. The alignment analysis shows the docked conformations are similar to co-crystal structures in the Protein Data Bank. Root-mean-square-deviation and fluctuation (RMSD and RMSF) analysis show that all simulations converge at 45 ns, with some regions exhibiting differential flexibility. Hydrogen bond analysis across 100 ns simulations show that ABL has one main H-bond, KIT has three main H-bonds, and SRC has no main H-bonds. All the drug-kinase complexes feature at least 15 key salt bridge interactions relevant for structural stability. The dihedral distributions reveal that most residues adopt a single conformation, but some can adopt multiple, increasing the protein flexibility. The entropy results quantify the protein disorder, revealing KIT and SRC favors the apoprotein while ABL favors the complex. This signifies that broad protein similarity does not govern imatinib binding, instead, it is explained by smaller structural details.

A simplified molecular-dynamics-based electronic circular dichroism (ECD) approach was tested on three condensed derivatives with limited conformational flexibility and an isochroman-2H-chromene hybrid, the ECD spectra of which could not be precisely reproduced by the conventional ECD calculation protocol. Application of explicit solvent molecules at the molecular mechanics (MD) level in the dynamics simulations and subsequent TDDFT-ECD calculation for the unoptimized MD structures was able to improve the agreements between experimental and computed spectra. Since enhancements were achieved even for molecules with limited conformational flexibility, deformations caused by the solvent molecules and multitudes of conformers produced with unoptimized geometries seem to be key factors for better agreement. The MD approach could confirm that aggregation of the phenanthrene natural product luzulin A had a significant contribution to a specific wavelength range of the experimental ECD. The MD approach has proved that dimer formation occurred in solution and this was responsible for the anomalous ECD spectrum. The scope and limitations of the method have also been discussed.

The three-dimensional structure of DiB3, a fluorescent noncovalent complex of a genetically engineered variant of the bacterial protein lipocalin Blc with the synthetic GFP-like chromophore M739, was determined by molecular mechanics calculations. Compared to the crystal structure of the related DiB1 complex, an alternative binding site for the M739 chromophore was identified in the structure of the DiB3 complex. [ABSTRACT FROM AUTHOR]

The popularity of the Python programming language in chemistry is growing every year. Python provides versatility, simplicity, and a rich ecosystem of libraries, making it the preferred choice for solving chemical problems. It is widely used for kinetic and thermodynamic calculations, as well as in quantum chemistry and molecular mechanics. Python is used extensively for laboratory automation and software development. Data analysis and visualization in chemistry have also become easier with the libraries available in Python. The evolution of theoretical and computational chemistry is expected in the future, especially at intersections with other fields such as machine learning. This review presents tools developed for applications in kinetic, thermodynamic, and quantum chemistry, instruments for molecular mechanics, and laboratory equipment. Online courses that help scientists without programming experience adapt Python to their chemical problems are also listed. [ABSTRACT FROM AUTHOR]

In the present work, Pro-Gly glyproline and its biologically active complexes with heparin and with the antithrombin-heparin protein complex have been studied using molecular modelling methods. This molecule is used as a drug and exhibits antithrombotic, anticoagulant immunomodulatory, antiulcer, and antidiabetic effects. The conformational profiles of the dipeptide were studied within the molecular mechanics framework, the geometry and energy of intra- and interresidual interactions were estimated for the most stable states of the investigated dipeptide. A comparative analysis of the extended and folded structures of this molecule optimized by the DFT/B3LYP/6-31 G(d,p) method was carried out, the frontier molecular orbitals were calculated, the surface of the molecular electrostatic potential was studied, the effective charges on the atoms were determined, and the dipole moment and polarizability values were calculated. Molecular docking revealed that the folded structure of Pro-Gly glyproline showed a higher affinity value for both heparin and the antithrombin-heparin protein complex. A model of the pharmacophore of the Pro-Gly molecule for its interaction with a specific receptor was proposed. The obtained data form the basis for the development of effective analogs of glyprolines in the complex with heparin, which are more specific concerning their putative target—antithrombin. [ABSTRACT FROM AUTHOR]

The present study of biologically active Val-Trp dipeptide has been performed using computer modeling methods. To search the stable structures the different theoretically possible conformations of this molecule were calculated within molecular mechanics framework. The results showed that two types of conformations, folded and extended, are realized for this compound. Afterwards, the most stable conformations of the Val-Trp dipeptide were optimized using DFT/B3LYP level of theory with 6-31+G(d,p) basis set. The geometry, energy parameters, electronic properties, molecular electrostatic potential (MEP) map, highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies, chemical reactivity descriptors, nonlinear optical properties such as the electric dipole moment and polarizability were computed and compared for the optimized extended and folded structures of this molecule. The differences in the electronic structure between two characteristic conformations of title dipeptide were revealed. It was found the redistribution of charges as a result of folding of the peptide chain leads to a decrease in the dipole moment of this molecule. The effects of intramolecular hydrogen bonding on geometry of Val-Trp dipeptide were observed. [ABSTRACT FROM AUTHOR]

Background: Force fields are used in a wide variety of contexts for classical molecular simulation, including studies on protein-ligand binding, membrane permeation, and thermophysical property prediction. The quality of these studies relies on the quality of the force fields used to represent the systems. Methods: Focusing on small molecules of fewer than 50 heavy atoms, our aim in this work is to compare nine force fields: GAFF, GAFF2, MMFF94, MMFF94S, OPLS3e, SMIRNOFF99Frosst, and the Open Force Field Parsley, versions 1.0, 1.1, and 1.2. On a dataset comprising 22,675 molecular structures of 3,271 molecules, we analyzed force field-optimized geometries and conformer energies compared to reference quantum mechanical (QM) data. Results: We show that while OPLS3e performs best, the latest Open Force Field Parsley release is approaching a comparable level of accuracy in reproducing QM geometries and energetics for this set of molecules. Meanwhile, the performance of established force fields such as MMFF94S and GAFF2 is generally somewhat worse. We also find that the series of recent Open Force Field versions provide significant increases in accuracy. Conclusions: This study provides an extensive test of the performance of different molecular mechanics force fields on a diverse molecule set, and highlights two (OPLS3e and OpenFF 1.2) that perform better than the others tested on the present comparison. Our molecule set and results are available for other researchers to use in testing.

Functionalized nanotubes (NTs), nanosheets, nanorods, and porous organometallic scaffolds are potential in vivo carriers for cancer therapeutics. Precise delivery through these agents depends on factors like hydrophobicity, payload capacity, bulk/surface adsorption, orientation of molecules inside the host matrix, bonding, and nonbonding interactions. Herein, we summarize advances in simulation techniques, which are extremely valuable in initial geometry optimization and evaluation of the loading and unloading behavior of encapsulated drug molecules. Computational methods broadly involve the use of quantum and classical mechanics for studying the behavior of molecular properties. Combining theoretical processes with experimental techniques, such as X-ray crystallography, NMR spectroscopy, and bioassays, can provide a more comprehensive understanding of the structure and function of biological molecules. This integrated approach has led to numerous breakthroughs in drug discovery, enzyme design, and the study of complex biological processes. This short review provides an overview of results and challenges described from erstwhile investigations on the molecular interaction of anticancer drugs with nanocarriers of different aspect ratios.

Polyethylene terephthalate (PET) is the largest produced polyester globally, and less than 30% of all the PET produced globally (∼6 billion pounds annually) is currently recycled into lower-quality products. The major drawbacks in current recycling methods (mechanical and chemical), have inspired the exploration of potentially efficient and sustainable PET depolymerization using biological approaches. Researchers have discovered efficient PET hydrolyzing enzymes in the plastisphere and have demonstrated the selective degradation of PET to original monomers thus enabling biological recycling or upcycling. However, several significant hurdles such as the less efficiency of the hydrolytic reaction, low thermostability of the enzymes, and the inability of the enzyme to depolymerize crystalline PET must be addressed in order to establish techno-economically feasible commercial-scale biological PET recycling or upcycling processes. Researchers leverage a synthetic biology-based design; build, test, and learn (DBTL) methodology to develop commercially applicable efficient PET hydrolyzing enzymes through 1) high-throughput metagenomic and proteomic approaches to discover new PET hydrolyzing enzymes with superior properties: and, 2) enzyme engineering approaches to modify and optimize PET hydrolyzing properties. Recently, in-silico platforms including molecular mechanics and machine learning concepts are emerging as innovative tools for the development of more efficient and effective PET recycling through the exploration of novel mutations in PET hydrolyzing enzymes. In-silico-guided PET hydrolyzing enzyme engineering with DBTL cycles enables the rapid development of efficient variants of enzymes over tedious conventional enzyme engineering methods such as random or directed evolution. This review highlights the potential of in-silico-guided PET degrading enzyme engineering to create more efficient variants, including Ideonella sakaiensis PETase (IsPETase) and leaf-branch compost cutinases (LCC). Furthermore, future research prospects are discussed to enable a sustainable circular economy through the bioconversion of PET to original or high-value platform chemicals.

Six novel borophosphonate cube (–B 4 P 4 O 12 –) based covalent organic frameworks (BP-COFs) with high-connectivity have been computationally designed and proposed as CH 4 /H 2 adsorption and separation media. The structural characterization reflects that six BP-COFs own high porosity, low density, applicable pore size, large pore volume and accessible surface area which are beneficial to gas adsorption. The adsorption isotherms for H 2 at 77 K and 298 K and for CH 4 at 298 K were obtained with grand canonical Monte Carlo (GCMC) simulations. The results reveal that BP-COF-10, -11 and −12 possess the higher CH 4 and H 2 adsorption capacity versus BP-COF-7, -8 and -9. The CH 4 /H 2 adsorption separation simulation indicated that BP-COF-7, -8 and -9 owns the better CH 4 /H 2 selectivity than BP-COF-10, -11 and −12 at 298 K. It is excited that both CH 4 /H 2 adsorption capacity and selectivity of six BP-COFs are comparable to porous materials owing excellent gas adsorption and separation capacity. We expect this study may motivate researchers' efforts to develop new high-performance gas adsorption/separation material. • Structures of six high-connectivity COFs are designed and characterized in theory. • Simulation reveals excellent CH 4 /H 2 adsorption and separation properties of six COFs. • Relationships between structure and adsorption/separation properties are studied. [ABSTRACT FROM AUTHOR]

The development of ideas about the 3D structure of DNA and the mechanisms of its formation, from the discovery of the double helix to the present day, is considered. Methods of modeling the 3D structure at different steps of the study of the central molecule of life are reviewed. The results of calculations of intra- and intermolecular interactions among macromolecule subunits provide grounds for the discussion of the marvelous expediency in DNA molecular structure and its adaptability to important biological functions. New data about the substantial contribution of the chemically monotonous and conformationally flexible sugar-phosphate backbone to the formation of the sequence-dependent 3D structure of DNA are presented. The conformational diversity of DNA manifests itself in both the formation of duplexes (and even triplexes or quadruplexes) with different base pair geometries and the formation of duplexes with Watson–Crick nucleoside pairs containing local conformations falling into different regions of the torsion angles of the sugar-phosphate backbone, i.e., different conformational classes. According to our calculations, these classes can be divided into two groups. One of them includes local conformations in which torsion angles are close to one of the energy minimums of the isolated elementary repeating fragment, while the second group consists of conformations where one or more of these angles deviate from that of the nearest energy minimum by more than 30°. The patterns of the formation of local 3D structures in these two groups differ significantly. [ABSTRACT FROM AUTHOR]

Prismanes have been attracting interest for nearly 50 years because of their geometric symmetry, highly strained structures, and unique applications due to their high carbon densities and bulky structures. Although [3]-, [4]-, and [5]-prismanes have been synthesised, [6]-prismanes and their derivatives remain elusive. Herein, fluorine chemistry, molecular mechanics, molecular orbital package, and density functional theory calculations were used to design and implement the photoisomerisation of octafluoro[2.2]paracyclophane (selected based on the good overlap of its lowest unoccupied molecular orbitals and short distance between the benzene rings) into octafluoro-[6]-prismane. Specifically, a dilute solution of the above precursor in CH3CN/H2O/dimethyl sulfoxide (DMSO) (2:1:8, v/v/v) solution was irradiated with ultraviolet light, with the formation of the desired product confirmed through the use of nuclear magnetic resonance spectroscopy and gas chromatography–mass spectrometry. The product was thermally stable in solution but not under work-up conditions, which complicated the further analysis and single-crystal preparation. The key criteria for successful photoisomerisation were the presence of fluorine substituents in the cyclophane structure and DMSO in the solvent system. A more stable derivative design requires the isolation of prismane products. The proposed fluorination-based synthetic strategy is applicable to developing novel high-strain molecules/materials with three-dimensional skeletons.

(-)-Menthol has been widely used in clinical medicine, flavor, and fragrance. However, high volatility, short retention time, low solubility in water, and whisker growth of menthol are crucial problems for its application. In this paper, (-)-menthol-β-cyclodextrin inclusion complex was fabricated to solve these problems. The product was characterized by X-ray diffraction, Fourier transform infrared spectroscopy and thermogravimetric analysis. The results showed that menthol was successfully encapsulated in the cavity of β-cyclodextrin. Menthol itself vaporized almost completely at around 120 oC, while the maximum menthol release rate occurred at 267.5 oC after the formation of the inclusion complex. The stability and retention time were improved. The menthol release reaction order, apparent activation energy and the pre-exponential factor were obtained and their values were 0, 142.9 kJ/mol and 1.6 × 1013 respectively. The structure of menthol-β-cyclodextrin inclusion complex was investigated by molecular simulation and the minimum energy, –116.7 kJ/mol, was obtained at –0.8 × 10–10 m.

It is an established paradigm in the emerging fields of nanoscience, nanotechnology and molecular engineering that a very important domain of fundamental research is associated with carbon-based materials. Ever since the discovery of the first member of the fullerene family (C 60) in 1985, and the subsequent discovery of the other members, fullerenes as a nanoscopic allotrope of carbon with anticipated extensive applications in all areas of nanoscience and nanotechnology (both industrial and medical), materials science and engineering, condensed matter physics and chemistry have occupied a central position in research activities across the globe. Detailed investigations, both experimental and theoretical/computational, into their morphology, mechanical, thermal, chemical, biological, electronic, optical and structural properties have led to the emergence of a well-established and independent science of fullerenes, providing very valuable information both in basic and applied sciences. A comprehensive review of these properties of fullerenes, particularly their applications in the above fields will provide valuable up-to-date and essential background information for engaging in new research in this field and also be able to develop new concepts and applications of these exotic carbon structures. For instance, a recent development is their applications in the emerging field of nanoneuroscience, a field interfacing nanoscience and neuroscience. In this extensive, albeit selective survey, related mainly to the C 60 fullerenes, the processes involving their experimental synthesis, theoretical formulation of their geometrical structures, their mechanical and thermal properties and nanomedical applications have been reviewed and summarized both within the experimental and theoretical/computational domains. Essential theoretical concepts, ranging from discrete atomistic molecular dynamics and molecular mechanics methods to continuum-based methods have been expounded in order to facilitate the pursuance of the reviewed literature and also to aid in the development of further research in this field. [ABSTRACT FROM AUTHOR]

Computer-aided drug design is a powerful and promising tool for drug design and development, with a reduced cost and time. In the current study, we rationally selected a library of 34 fused imidazo[1,2-a]quinoxaline derivatives and performed virtual screening, molecular docking, and molecular mechanics for a lead identification against tubulin as an anticancer molecule. The computational analysis and pharmacophoric features were represented as 1A2; this was a potential lead against tubulin, with a maximized affinity and binding score at the colchicine-binding site of tubulin. The efficiency of this lead molecule was further identified using an in vitro assay on a tubulin enzyme and the anticancer potential was established using an MTT assay. Compound 1A2 (IC50 = 4.33–6.11 µM against MCF-7, MDA-MB-231, HCT-116, and A549 cell lines) displayed encouraging results similar to the standard drug colchicine in these in vitro studies, which further confirmed the effectiveness of CADD in new drug developments. Thus, we successfully applied the utility of in silico techniques to identify the best plausible leads from the fused azaheterocycles. [ABSTRACT FROM AUTHOR]

Enzyme design is an important application of computational protein design (CPD). It can benefit enormously from the additional chemistries provided by noncanonical amino acids (ncAAs). These can be incorporated into an 'expanded' genetic code, and introduced in vivo into target proteins. The key step for genetic code expansion is to engineer an aminoacyl-transfer RNA (tRNA) synthetase (aaRS) and an associated tRNA that handles the ncAA. Experimental directed evolution has been successfully used to engineer aaRSs and incorporate over 200 ncAAs into expanded codes. But directed evolution has severe limits, and is not yet applicable to noncanonical AA backbones. CPD can help address several of its limitations, and has begun to be applied to this problem. We review efforts to redesign aaRSs, studies that designed new proteins and functionalities with the help of ncAAs, and some of the method developments that have been used, such as adaptive landscape flattening Monte Carlo, which allows an enzyme to be redesigned with substrate or transition state binding as the design target. [ABSTRACT FROM AUTHOR]

Using examples of an exothermic chemical reaction and self-heating of the region of a conducting filament of a memristor, heat-induced phase transitions, disadvantages of applying the classical Fourier approach on the nanoscale, and advantages of the molecular mechanics method at modeling the temperature factors are discussed. The correction for the Arrhenius relationship, taking into account the fact that the temperature becomes a random variable is proposed. Based on the introduced concepts (elementary act of heat release, as well as the distance and region of thermal impact), a methodology for taking into account the thermal factor is proposed. The correction is based on splitting the entire pool of particles into several flows, each of which corresponds to a fixed temperature value taken from a certain range. Although both continuous and discrete correction options are given, the discrete option is preferable. This is due to the fact that the methodology focuses on the application of methods of molecular mechanics, and does so intentionally in the most primitive version. The role of amorphization is noted as an example of the structural restructuring of matter in nanovolumes. It is indicated that the phonon spectra themselves, which determine heat transfer, depend on temperature. The technique is consistent with the ideology of multiscale modeling. The integral temperature increase is calculated outside the region of thermal exposure, where nonequilibrium effects are significant, by solving the standard equation of thermal conductivity. [ABSTRACT FROM AUTHOR]

Commercial carbazole derivatives are widely used as typical electron donors in room‐temperature phosphorescence materials. The high phosphorescence quantum yield (Φp) and short lifetime (τp) of the carbazole‐based (9H‐carbazol‐9‐yl)isonicotinonitrile (P‐34N) crystal are distinguished by quantum mechanics and molecular mechanics method. Two inducements are accounted for the high Φp of P‐34N: i) large spin–orbit coupling (0.63 cm−1) induces fast intersystem crossing (ISC) of the lowest singlet excited state (S1) to the lowest triplet excited state (T1), ii) the intermolecular π–π interactions stabilize triplet excitons. Meanwhile, the 3(n, π*) →1(π, π*) of P‐34N favors the nonradiative decay of T1to the ground state (S0), and thus, causes short τp. In contrast to P‐34N, the low Φp of 6‐(9H‐carbazol‐9‐yl)nicotinonitrile (P‐24N) crystal results from the effective reverse ISC process induced by small ΔEST (0.3 eV) between S1 state and the higher triplet state (T2), and the long τp is due to the unfavorable orbital reversals of T1 (π, π*)→S0 (π, π*) transition and the internal conversion process of T2 → T1. This work presents a reasonable interpretation of the Φp and τp of two carbazole‐based crystals. [ABSTRACT FROM AUTHOR]

Carbon nanotubes (CNTs) are widely used as reinforcements in cement-based composites. The improvement in the mechanical properties of the resulting materials depends on the characteristics of the interface formed between CNTs and the cement matrix. The experimental characterization of the interfacial properties of these composites is still limited and hard to achieve with currently available technologies. In this work, molecular dynamics and molecular mechanics pull-out simulations of pristine and functionalized CNTs, taken from a tobermorite crystal, were carried out to study interfacial shear strength (ISS) from an atomic perspective. ISS was calculated from the potential energy of the systems. The effects of the CNT diameter and the degree of functionalization on the pull-out process were analyzed according to the ISS and non-bonded energy results. The influence of H-bonding and electrostatic interactions between the CNT and the matrix were also studied. The results show that ISS decreases with increasing CNT radius for pristine CNTs and depends upon the number of H-bonds for functionalized CNTs. ISS values are positively correlated to Enon-bonded energy, which is related to the number of carboxyl groups on the CNT surface. A high degree of functionalization increases both the number of H-bonds and the number of Ca2+-O interactions between the CNT and the tobermorite surface. This results in a stronger interfacial interaction and, therefore, an elevated ISS value. [ABSTRACT FROM AUTHOR]

[Display omitted] • Optimized GbD encapsulation via MD simulations, enhancing bioavailability with γ-CD derivatives. • Octakis(6-O-sulfo)-γ-CD/GbD shows superior stability, driven by favorable Gibbs free energy. • IGMH analysis reveals maximal non-covalent interactions in the Octakis-γ-CD/GbD complex. • Temperature stability study confirms robust GbD inclusion in Octakis(6-O-sulfo)-γ-CD. Glabridin (GbD), a plant-derived bioactive molecule, exhibits diverse biological activities as documented in the literature. However, its low aqueous solubility limits its clinical utility and bioavailability. This study extensively screened β-cyclodextrin (β-CD), γ-CD, and their derivatives to identify the optimal CD for GbD encapsulation to enhance its bioavailability. Molecular dynamics simulations were performed on all docked inclusion complexes (ICs), with selection based on binding energy scores derived via the MM/PBSA method. The selected complexes, γ-CD/GbD and Octakis(6-O-sulfo)-γ-CD/GbD-1, underwent robust umbrella sampling simulations and quantum mechanics calculations using the DFT method (wB97X-D/6-311 + G(d,p)) to determine their thermodynamics. Additionally, MD simulations of the most stable ICs were conducted over a temperature range of 35 °C to 75 °C to assess temperature-dependent structural stability. The analysis revealed higher stability for the Octakis(6-O-sulfo)-γ-CD/GbD-1 complex, attributed to its more favorable Gibbs free energy (−349.92 kJ/mol) compared to γ-CD/GbD (−141.18 kJ/mol). The primary focus of the research was to maximize non-covalent interactions by selecting the appropriate CD form, with Octakis(6-O-sulfo)-γ-CD exhibiting the highest number of non-covalent interactions as elucidated by the IGMH method. Consequently, the Octakis(6-O-sulfo)-γ-CD/GbD-1 IC in 1:1 stoichiometry presents a promising strategy for the future clinical application of GbD. [ABSTRACT FROM AUTHOR]

Piperine (PiP), a bioactive molecule, exhibits numerous health benefits and is frequently employed as a co-delivery agent with various phytomedicines (e.g., curcumin) to enhance their bioavailability. This is attributed to PiP's inhibitory activity against drug-metabolizing proteins, notably CYP3A4. Nevertheless, PiP encounters solubility challenges addressed in this study using cyclodextrins (CDs). Specifically, γ-CD and its derivatives, Hydroxypropyl-γ-CD (HP-γ-CD), and Octakis (6-O-sulfo)-γ-CD (Octakis-S-γ-CD), were employed to form supramolecular complexes with PiP. The conformational space of the complexes was assessed through 1 μs molecular dynamics simulations and umbrella sampling. Additionally, quantum mechanical calculations using wB97X-D dispersion-corrected DFT functional and 6–311 + G(d,p) basis set were conducted on the complexes to examine the thermodynamics and kinetic stability. Results indicated that Octakis-S-γ-CD exhibits superior host capabilities for PiP, with the most favorable complexation energy (−457.05 kJ/mol), followed by HP-γ-CD (−249.16 kJ/mol). Furthermore, two conformations of the Octakis-S-γ-CD/PiP complex were explored to elucidate the optimal binding orientation of PiP within the binding pocket of Octakis-S-γ-CD. Supramolecular chemistry relies significantly on non-covalent interactions. Therefore, our investigation extensively explores the critical atoms involved in these interactions, elucidating the influence of substituted groups on the stability of inclusion complexes. This comprehensive analysis contributes to emphasizing the γ-CD derivatives with improved host capacity. [Display omitted] [ABSTRACT FROM AUTHOR]