Journal of Computational Biophysics and Chemistry

In the past decade, there has been an extensive advancement in the creation of methods for the design and prediction of protein structures. Expeditious growth in protein structure and sequence databases has charged the development of computational approaches for the prediction of structures. This review focuses on fragment-based strategy, a computational approach for the prediction of the three-dimensional structure of proteins. Fragment assembly has immensely improved protein structure prediction accuracy, especially of the single-domain proteins at the fold level. Fragment libraries are generated using the dihedral angles along with local structural information of known protein structures. This leads to the construction of a full-length polypeptide chain of a query protein using the fragments present in these libraries. The energy function of the proteins is minimized contributing to multiple conformations considering the backbone atoms and “centroid” side-chain pseudo-atoms using conformational sampling. Lastly, Monte Carlo simulation is performed for the sampling of the side-chain rotamers and reduction of energy for more precise and refined model construction. The quality of the fragments determines whether the native-like conformations generated are accurate or not. The future direction as well as tools like ROSETTA, QUARK, FRAGFOLD, M-TASSER, and AlphaFold2 that use fragment assembly for optimal structure prediction have also been described and compared in this review.

Cubic Zirconia (CZ) has emerged as a critical material with diverse applications, ranging from high-performance ceramics to electronic devices. Designing CZ-based systems with improved functions necessitates a thorough understanding of its topological characteristics. The topological co-indices are numerical descriptors that offer important details about the local atomic configurations and connectivity inside the CZ lattice. In this study, we present a methodical approach to compute and assess the distribution of these co-indices throughout the CZ network using advanced computational approaches. The distribution patterns of topological co-indices inside the CZ network are significantly better understood as a result of our statistical investigation. The basic knowledge of the topological properties of the CZ network and how they relate to physical properties is improved by this study.

Empirical force field methods typically rely on point charges to describe the electrostatic interactions, which is problematic when anisotropy needs to be considered, as in the case of the electrostatic potential of covalently bound halogens that possess a positive site, termed $\sigma$-hole, surrounded by a large negative belt. To address this, an off-center point charge (extra point, EP) is usually placed at a given distance from the halogen to emulate the $\sigma$-hole and commonly used implementations are based on the restrained electrostatic potential (RESP) procedure to fit atomic charges, being one of the most used charge models. In this context, no specific Merz–Singh–Kollman (MK) radius for iodine is available in the literature, which is an essential parameter in the RESP fitting procedure. In this work, we explored the impact of the iodine MK radius on the obtained RESP charges for a set of 12 iodinated molecules. We verified that the relative root mean square (RRMS) values obtained with and without an EP kept decreasing with increasing radii for most compounds, thus impairing optimization using such a procedure. Nevertheless, the use of an iodine MK radius lower than 2 Å is not advisable since the RRMS kept decreasing considerably until this value was reached. Moreover, the performance of three iodine MK radii was studied with the estimation of the free energy of hydration ($\mathrm{\Delta }{G}_{\text{hyd}})$ values using alchemical free energy calculations, which are particularly sensitive to the charges used. Despite the usage of different radii not leading to remarkable differences, our results indicate that using a value of 2.70 Å leads to lower mean absolute errors (MAE) and root mean squared error (RMSE) values when comparing the calculated with the experimental $\mathrm{\Delta }{G}_{\text{hyd}}$ values.

Actin is a highly conserved cytoskeletal protein that is present in all eukaryotes. Polymerization of actin to filamentous actin is essential for numerous cellular processes. Abnormal actin dynamics are directly associated with a variety of diseases, including cancer, immunological and neurological disorders. However, the dynamics of actin are not fully understood. In this work, we study the effects of nucleotides and metal ions on conformation of F/G-actin using molecular dynamics (MD) simulations. Our results show that different nucleotides and metal ions change the conformation of actin. The state of Adenosine Triphosphate (ATP) binding on F-actin conformation is more stable than G-actin. The D-loop has a large fluctuation when ${\text{Ca}}^{2+}$ binds to G-ATP-actin than ${\text{Mg}}^{2+}$ binds. Adenosine Diphosphate (ADP) binding leads to a stronger residual correlation on F-actin conformation, while it is opposite on G-actin. In addition, the detailed interactions between nucleotides and adjacent residues are discussed on different states of actin. This work provides a structural basis for understanding how the different nucleotides/metal ions binding influences the conformation of actin.

In the overall aromaticity of a molecular system, the magnitude of $\sigma$-aromaticity influences the degree of bond length averaging in the molecular geometry, while the magnitude of $\pi$-aromaticity reflects the strength of $\pi$-electron delocalization, subsequently affecting the electronic transport properties of the entire molecular system. Simultaneously, the aromaticity type of a molecular system is primarily determined by the symmetry of the innermost $\pi$ molecular orbitals. In this study, we conducted computational simulations of the aromaticity and electronic transport properties of compounds, including C₈H₈Cu₂ with $p_{\pi }$–$d_{\pi }$ delocalization effects and C₁₂H₈ with $p_{\pi }$–$p_{\pi }$ delocalization effects, along with their Li derivatives. Based on calculated NICS values, ring current directions, molecular structural configurations and the symmetry of the innermost $\pi$ molecular orbitals, we clarified the aromaticity types of the molecular systems. Combined with the analysis of molecular electrical conductivity properties, we gained insights into the fundamental attributes of Li-bridge bonds in Li derivatives and the factors influencing electronic transport pathways. Consequently, we established a relationship between the aromaticity of molecular systems and their electronic transport properties. To a certain extent, a novel criterion for evaluating molecular aromaticity is proposed from the perspective of single-molecule electronics.

In this study, a new series of 1,3,4-oxadiazole derivatives (3a– 3h) was synthesized, characterized using various analytical techniques (FT-IR, ¹H- and ${}^{13}$C-NMR, mass spectrometry), and tested for their effectiveness against Ehrlich’s Ascites Carcinoma (EAC) cell lines in vitro. After 48 h of exposure to these test compounds, the EAC cells exhibited a dose-dependent reduction in their viability. Among the tested compounds, 3b and 3e demonstrated the most potent anticancer effects, with IC${}_{50}$ values of 352.69 $\mu$M and 177.44 $\mu$ M, respectively. Consequently, these compounds were chosen for further investigation into their mechanisms of action on EAC cell lines. The assessment included the induction of apoptosis and the analysis of DNA damage, which were evaluated using fluorescence staining and the comet assay. These assessments revealed distinctive apoptotic characteristics such as nuclear fragmentation, cytoplasmic shrinkage and DNA damage. As a result, these compounds hold promise as potential anticancer agents. The study also delved into the binding affinities of these compounds through molecular docking analysis, and the findings showed that compounds 3b and 3e exhibited a strong binding affinity with the receptor Transforming Growth Factor-Beta Receptor I (TGF-$\beta$RI) kinase (PDB ID: 1PY5), surpassing the reference compound 5-fluorouracil. Additionally, calculations related to Molecular Mechanics Generalized Born Surface Area (MM-GBSA) indicated favorable free binding energy. The compounds also displayed acceptable ADMET properties. To validate the stability of the bond between compounds 3b and 3e with the 1PY5 receptor, a molecular dynamics simulation lasting 100 ns was carried out.

Herein, we report the design of a new set of pyrazine-2-carbohydrazide derivatives (T1–T20) and in silico investigations to evaluate their inhibition activity against the enzyme, decaprenylphosphoryl-$\beta$-D-ribose 2^′-epimerase (DprE1). The derivatives interact with the Cys387 residue of the enzyme’s active site through hydrogen bonds. Further, we synthesized these compounds and evaluated their efficacy against the M. tuberculosis H37Rv strain. Compounds T16 and T19 displayed promising antitubercular activity, boasting a minimal inhibitory concentration of 1.56 $\mu$g/mL. Furthermore, we assessed the antibacterial activity of these compounds against a range of pathogens, including S. aureus, S. mutans, E. coli and $S.$Typhi. Additionally, we evaluated their antifungal potency against A. niger. Notably, compounds T4, T8, T9, T16 and T19 exhibited noteworthy antibacterial activity against tested bacterial strains. Compounds T4, T9, T16, T17, T18 and T19 showed significant inhibition activity against A. niger. Importantly, all active compounds demonstrated low cytotoxicity, with IC₅₀ values exceeding 300 $\mu$M, ensuring no harm to normal cells. To gain a deeper understanding of these compounds, we conducted in silico investigations to evaluate their pharmacokinetics and pharmacochemical properties. Additionally, we employed DFT studies to explore the electronic characteristics of these compounds, providing valuable insights into their potential applications in the pharmaceutical field.

Overcoming the acquired C797S mutation in nonsmall cell lung cancer (NSCLC) represents a great challenge for EGFR tyrosine kinase inhibitors (TKIs). BLU-945 is a promising fourth-generation EGFR TKI undergoing clinical trials, with different binding conformation from other known EGFR TKIs. In this study, we explored the binding mode of a BLU-945 analog (BLU) with wild-type and mutant EGFRs using $\mu$s-scale molecular dynamics. The results show that Met793 at the hinge region is the critical binding site for BLU as observed in other known EGFR inhibitors. The occupancy of hydrogen bonds with Met793 is lower in wild-type EGFRs than in mutant EGFRs. Meanwhile, Thr854 contributes largely to the hydrogen bond formation for triple mutant EGFR compared to wild-type EGFR. Energy decomposition reveals that Leu718 and Leu844 dominate the energy contribution. T790M mutation plays an important role in BLU binding with wild-type and mutant EGFRs. Dynamic network analysis indicates that Arg841 behaves differently in triple mutant EGFR compared to wild-type, single and double mutant EGFRs, confirmed by further analysis of salt-bridge formation. Our study may provide beneficial information for developing fourth-generation EGFR TKIs.