Journal of Biomolecular Structure & Dynamics最新文献

Keratin derived from human hair has garnered significant attention for its biomedical applications. While ionic liquids (ILs) and keratinases independently facilitate hair hydrolysis, their synergistic use remains largely unexplored. Here, we computationally investigate the possibility of combining the use of ionic liquids and keratinases. We present here the structure of kerF and kerC, two keratinases identified from literature as promising candidates for human hair degradation, predicted using AlphaFold2. Subsequently, we performed molecular dynamics simulations to investigate the stability of these keratinases in water and six ionic liquids, chosen based on their recorded human hair degradation efficiency. The stability analysis was conducted using key metrics such as root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent accessible surface area (SASA), and number of intra-protein hydrogen bonds. Computational data indicate that kerF exhibits stability in both water and two ionic liquids: 1-Allyl-3-methylimidazolium chloride [AMIM]Cl, and 1-butyl-3-methylimidazolium bromide [BMIM]Br. kerC remains stable in [AMIM]Cl. The results suggest the potential utility of these two keratinases in environmentally friendly keratin extraction processes from human hair waste. This study aims to identify suitable keratinases and advances the understanding of their stability in non-conventional ionic liquid solvent systems, supporting the development of sustainable, eco-friendly strategies for the extraction of valuable human hair keratin.

This theoretical study examines the interaction between dacarbazine (DTIC) and a select group of amino acids-lysine (Lys), histidine (His), threonine (Thr), and isoleucine (Ile)-utilizing density functional theory (DFT) calculations. The research offers a comprehensive analysis of the noncovalent interactions that dictate the stability of DTIC-amino acid complexes, including hydrogen bonding, electrostatic forces, and hydrophobic contacts. The findings indicate that hydrogen bonding plays a crucial role in stabilizing these complexes, with the DTIC-His interaction demonstrating the highest stability energy of -19.89 kcal/mol. Natural bond orbital (NBO) calculations further substantiate this observation, revealing a significant second-order perturbation energy of 34.55 kcal/mol, highlighting the strong electronic interactions between DTIC and histidine. Additional insights from the Quantum Theory of Atoms in Molecules (QTAIM) and global reactivity descriptors affirm the presence of robust hydrogen bonds, particularly in the DTIC-His complex. The study also investigates the optical properties of these complexes through UV-vis calculations, identifying distinct characteristic wavelengths. Notably, the DTIC-His complex absorbs at 321.36 nm, while DTIC-Ile exhibits absorption at 329.61 nm. This research underscores the critical role of histidine in binding to dacarbazine, providing quantitative insights into the binding affinities and electronic properties of these interactions. These findings enhance the understanding of the molecular mechanisms underlying DTIC-amino acid complexes, with potential implications for drug design and biochemical applications.

The cellular immune responses associated with multiple sclerosis are triggered when T-lymphocyte receptors interact with the MOG epitope-MHC complex. By inhibiting the formation of this harmful trimeric complex (MHC-epitope-TCR), it is possible to alleviate the symptoms of MS. In this research, one of the human neuroantigenic epitopes (hMOG_37-46) involved in MS was bound to mouse MHC, forming a dimer complex (mMHC-hMOG). Subsequently, 12 peptides derived from honey bee venom were selected. Each peptide underwent a separate 100 ns molecular dynamics (MD) simulation before being docked into the binding cleft of the dimer complex, facilitating the identification of the most favorable complex. These trimer complexes were then subjected to an additional 100 ns MD simulation, and the binding free energy for each bee peptide to the dimer complex was computed using the MM/PBSA and quasi-harmonic methods. The findings indicated that Secapin 53-77 (YIIDVPPRCPPGSKFIKNRCRVIVP) demonstrated a greater binding affinity to the dimer complex. An examination of the binding site for this peptide within the dimer complex revealed a close similarity to the binding site of MHC with TCR, suggesting that this bee peptide can effectively obstruct the interaction between the mMHC-hMOG complex and TCR, thus preventing the onset of MS-related reactions. Also, another MD simulation showed that this peptide can bind to the complex human MHC-human MOG properly. Furthermore, based on the simulation results, a novel peptide (YIIKVHHRCHHGSKVIKNRCRVIVH) was designed, which also exhibited favorable interactions with the mMHC-hMOG complex. Finally, the residence times of these two peptides were determined through RAMD simulation.

To date, the treatment for Alzheimer's disease (AD) has focused on the cholinergic hypothesis, particularly through the inhibition of acetylcholinesterase (AChE). Asiatic acid, madecassic acid, asiaticoside, and madecassoside, which are triterpenoid derivatives from Centella asiatica, have previously been reported to exhibit the AChE inhibitory activity. This study aimed to investigate their binding modes and to determine efficient computational methods for analyzing their interactions with AChE. Molecular dynamics simulations demonstrated that most of their equilibrated structures remained within the AChE binding site. Principal component analysis and free energy landscape (FEL) confirmed their stability of the binding. Among the evaluated methods, the MM-(ALPB)SA binding energies, when combined with ligand surface binding efficiency index, showed the best correlation with experimental binding free energy. Density functional theory (DFT) calculations revealed the common key interaction between triterpenoids and AChE, including hydrogen bonds (Tyr124, Arg296, Tyr337, and Tyr341), H-π (Tyr341) and van der Waals (Trp86) interactions. Additionally, pharmacokinetics and drug-likeness predictions indicated that madecassic acid and asiatic acid are promising candidates for drug development. This study highlights the potential of triterpenoid derivatives in AChE inhibition and provides valuable insights into their binding efficiency, which could contribute to future drug discovery targeting Alzheimer's disease.

Dengue virus, an arbovirus belongs to the Flavivirus genus is the causative agent of Dengue fever, Dengue Hemorrhagic fever and Dengue Shock Syndrome, and accounts for thousands of lives every year. Here, we have characterized three such Dengue virus proteins (NS2A, NS2B and M) which have been previously shown to possess porin like functions. An exhaustive review of the literature and multiple in silico techniques were used to identify the protein segments that are capable of generating pores. Using independent sets of Molecular Dynamics (MD) simulations and post-simulation assessments, followed by hydration analysis of the channel interiors, the potential oligomeric status of the pore-forming segments was determined. The most likely ion conducting conformation and oligomeric status were chosen after the ion conductivity mechanism of the various oligomeric topologies was examined using computational electrophysiology MD simulations. The structure of the ion channel topologies as well as their electrical characteristics, such as conductance and current through the channel, were thoroughly described. The structure-function link of the porin activity of the three Dengue virus proteins is explained in depth by this work. The data gathered from this investigation could assist target these proteins for therapeutic intervention and support future research on the ion channel function of the Dengue virus proteins.

Tuberculosis (TB) remains a major global health issue, with growing challenges posed by drug resistance, highlighting the urgent need to identify new drug targets. This study examines the conservation pattern of the dapB gene, which encodes Dihydrodipicolinate reductase (DapB), a key enzyme in the lysine biosynthesis pathway of Mycobacterium tuberculosis (Mtb), a pathway absent in humans. The dapB gene was amplified from 72 Indian clinical isolates, sequenced and analysed for mutations. Further, the genomic data of 310 isolates from the Bacterial and Viral Bioinformatics Resource Center (BV-BRC) database were also analysed. Further, atomistic simulations were performed in triplicate for the wild-type and mutant proteins to assess the impact of mutations on protein structure and function. Sequence analysis identified a single DapB mutation (DapB_65), among clinical isolates. Analysis of BV-BRC isolates revealed two synonymous mutations and one non-synonymous mutation (DapB_89). The mutations were mapped on the surface of the protein and were found to be more than 1.0 nm away from the active site. Simulations reveal no significant difference in the overall structure or the binding pocket dimensions and volumes between the native and mutant proteins. This study thus highlights the potential of DapB as a conserved drug target for future drug development efforts aimed at TB.

Human serum albumin (HSA) is the most abundant protein carrier found in blood. The level of glycated human serum albumin (GHSA) can be used as a diabetes biomarker. Therefore, many attempts have been made to design selective GHSA detection methods. GHSA has been found to show unique characteristics. Glycation has been found to impair albumin structure and function, where a microscopic explanation is limited. Thus, in this work, molecular dynamics simulations were performed to capture the structural and dynamic properties of GHSA in comparison to non-glycated albumin (HSA). A fully glycated albumin (experiment-reported 14 glycation sites) was used in this work. The changes in structural properties appear to be the root cause for functional impairment. The full glycation appears to cause: (i) the enhancement of protein flexibility and water exposure; (ii) the serious degrees of helical unfolding; (iii) the widening of drug site entrance; (iv) greater reactivity of C34 and (v) the severe alteration of fatty acid- and drug- binding cavities. Comparing with a single-site glycated albumin, the higher degrees of glycation appear to have more impact on protein structure and function. Our results can illustrate the key microscopic features that make GHSA differ from native HSA. This insight will aid in the design and development of selective and sensitive methods for GHSA detection.

This study investigated the effects of system temperature and type of solvent (water) on the process and mechanism of liposome formation. A mixture of DOPE (1, 2-dioleoyl-sn-glycero-3-phosphocholine) with negative curvature, and DOPC (1, 2-dioleoyl-sn-glycero-3-phosphoethanolamine), as no curvature phospholipids were utilized for the formation of liposomal structures. To assess the impact of temperature on the formation of liposomal structures, temperatures of 300 and 400 K were employed. Additionally, to investigate the effect of solvent type, both polar and non-polar coarse-grained water solvents were used. The results showed that DOPC and DOPE phospholipids formed bilayered spherical liposomal structures at both 300 and 400 K. However, the rate of liposome formation was higher at 400 K compared with 300 K (almost 3 times higher). This suggests that 400 K is the optimal temperature for enhancing the efficiency of liposome synthesis. Furthermore, the findings revealed that DOPC and DOPE phospholipids formed bilayered spherical liposomes and bilayered ellipsoidal liposomes in polar and non-polar coarse-grained water media, respectively. Both polar and non-polar coarse-grained water are suitable for liposome formation.

Human papillomavirus (HPV) is a well-established causative agent in cervical as well as in a few other anogenital and oropharyngeal cancers. Of the many genotypes, HPV16 and HPV18 are the most oncogenic, individually responsible for more than half of all cervical cancer cases worldwide. In the current study, a structure-based computational strategy was used to search for candidate small-molecule inhibitors for the E6 and E7 proteins of HPV16 and HPV18. A subset of ligands was subjected to molecular docking to assess their binding affinities at the oncoprotein active sites. Validation of structural stability of the docked complexes was carried out using molecular dynamics (MD) simulation and PCA based FEL analysis under physiological conditions. In addition, the ADMET and toxicity profiles of both compounds were also predicted with ProTox-III based on top parameters. This integrative overview allowed for the recognition of promising lead compounds possessing favorable binding properties, structural integrity, and low predicted toxicity.

Compatible osmolytes like trimethylamine N-oxide (TMAO), known for preferentially stabilizing proteins in their folded states, offer a potential solution; however, the precise molecular mechanisms underlying their stabilizing effects are not fully understood. On the other hand, the poor thermal stability of pharmaceutical enzymes such as urate oxidase (UOX) in aqueous solutions remains a significant challenge. This study explored how TMAO modulates the enzyme's environment to enhance UOX's catalytic efficiency and stability. By combining experimental and computational approaches, we evaluated the kinetic, thermodynamic, and structural changes in urate oxidase with and without the osmolyte. Kinetic analysis revealed enhanced enzymatic activity in the presence of TMAO. Thermodynamic studies indicated negative values for enthalpy change (ΔH°) and entropy change (ΔS°), suggesting the involvement of van der Waals forces and hydrogen bonding in UOX-TMAO interactions. The negative value of free energy change (ΔG°) further confirms spontaneous binding. Fluorescence spectroscopy indicated structural modifications in the enzyme due to osmolyte binding, supported by a complex quenching mechanism. Molecular dynamics (MD) simulations demonstrated that TMAO increased UOX's structural compactness and enzyme stability, along with a rise in secondary structure content, which helped preserve the integrity of the active site. Moreover, molecular docking revealed a favorable binding of TMAO to UOX, primarily mediated by non-covalent interactions, thereby corroborating our experimental findings. These findings provide atomic insights into how TMAO can improve the stability and catalytic function of UOX.