Targeted delivery of SN38 to breast cancer using amphiphilic diblock copolymers PHPMA-b-PBAEM as micellar carriers with AS1411 aptamer.

Breast cancer treatment can be challenging, but a targeted drug delivery system (DDS) has the potential to make it more effective and reduce side effects. This study presents a novel nanotherapeutic targeted DDS developed through the self-assembly of an amphiphilic di-block copolymer to deliver the chemotherapy drug SN38 specifically to breast cancer cells. The vehicle was constructed from the PHPMA-b-PEAMA diblock copolymer synthesized via RAFT polymerization. A single emulsion method was then used to encapsulate SN38 within nanoparticles (NPs) formed from the PHPMA-b-PEAMA copolymer. The AS1411 DNA aptamer was covalently bonded to the surface of the micellar NPs, producing a targeted DDS. Molecular dynamics (MD) simulation studies were also performed on the di block polymeric system, demonstrating that SN38 interacted well with the di block. The in vitro results demonstrated that AS1411- decorated SN38-loaded HPMA NPs were highly toxic to breast cancer cells while having a minimal effect on non-cancerous cells. Remarkably, in vivo studies elucidated the ability of the targeted DDS to enhance the antitumor effect of SN38, suppressing tumor growth and improving survival rates compared to free SN38.

New Perspective on the Interaction Behavior Between Riboflavin and ß Lactoglobulin-ß Casein Complex by Biophysical Techniques.

Riboflavin (RF) is a vitamin that only exists in plants and microorganisms and must be procured externally by humans. On the other hand, there are two major allergic factors in cow's milk, including ß-lactoglobulin (ßLG) and ß-casein (ßCN), while their allergic properties can be eliminated by binding to micronutrients. In this regard, we examined the binding process of RF to ßLG and ßCN in the binary and ternary systems by different spectroscopies such as zeta potential, electric conductivity, and molecular modeling. According to the result of the fluorescence spectrum regarding the interaction of RF with ßLG and ßCN in binary and ternary systems, an increase in RF concentration declined the fluorescence intensity of three systems and also caused the quenching of proteins. Static quenching plays a pivotal role in the formation of stable interactions. The obtained thermodynamic parameters by Van't Hoff equation ascertained the predominance of hydrogen bonds and van der Waals interaction in all the systems. Considering how the negative value of ΔH0 resulted in the negative value of ΔG0, the systems were assumed to be enthalpy driven. The outcomes of circular dichroism (CD) disclosed that the attachment of RF to the targets of systems increased their a-helix content, which particularly included the binding of RF to ßLG that led to the conversion of ß-sheet to α-helix content. As indicated by the results of zeta potential, the low concentration of RF contained the dominance of hydrophobic forces in the interactions, whereas the enlargement of this concentration prevailed electrostatic forces. Moreover, conductometry measurements showed an extension in the rate of ionizable groups due to the addition of RF to the systems, which may increase the probability of an interaction between RF, ßCN, and ßLG in binary and ternary systems. In consistency with the outcomes of molecular dynamics simulation, the data of molecular docking approved the capability of RF in forming strong and stable interactions with ßCN and ßLG.

Spectroscopy and molecular simulation on the interaction of Nano-Kaempferol prepared by oil-in-water with two carrier proteins: An investigation of protein-protein interaction.

In this work, the interaction of human serum albumin (HSA) and human holo-transferrin (HTF) with the prepared Nano-Kaempferol (Nano-KMP) through oil-in-water procedure was investigated in the form of binary and ternary systems by the utilization of different spectroscopy techniques along with molecular simulation and cancer cell experiments. According to fluorescence spectroscopy outcomes, Nano-KMP is capable of quenching both proteins as binary systems by a static mechanism, while in the form of (HSA-HTF) Nano-KMP as the ternary system, an unlinear Stern-Volmer plot was elucidated with the occurrence of both dynamic and static fluorescence quenching mechanisms in the binding interaction. In addition, the two acquired Ksv values in the ternary system signified the existence of two sets of binding sites with two different interaction behaviors. The binding constant values of HSA-Nano KMP, HTF-Nano-KMP, and (HSA-HTF) Nano-KMP complexes formation were (2.54 ± 0.03) × 104, (2.15 ± 0.02) × 104 and (1.43 ± 0.04) × 104M-1at the first set of binding sites and (4.68 ± 0.05) × 104 M-1 at the second set of binding sites, respectively. The data of thermodynamic parameters confirmed the major roles of hydrogen binding and van der Waals forces in the formation of HSA-Nano KMP and HTF-Nano KMP complexes. The thermodynamic parameter values of (HSA-HTF) Nano KMP revealed the dominance of hydrogen binding and van der Waals forces in the first set of binding sites and hydrophobic forces for the second set of binding sites. Resonance light scattering (RLS) analysis displayed the existence of a different interaction behavior for HSA-HTF complex in the presence of Nano-KMP as the ternary system. Moreover, circular dichroism (CD) technique affirmed the conformational changes of the secondary structure of proteins as binary and ternary systems. Molecular docking and molecular dynamics simulations (for 100 ns) were performed to investigate the mechanism of KMP binding to HSA, HTF, and HSA-HTF. Next to observing a concentration and time-dependent cytotoxicity, the down regulation of PI3K/AkT/mTOR pathway resulted in cell cycle arrest in SW480 cells.

Structure, Function, and Physicochemical Properties of Pore-forming Antimicrobial Peptides.

Antimicrobial peptides (AMPs), a class of antimicrobial agents, possess considerable potential to treat various microbial ailments. The broad range of activity and rare complete bacterial resistance to AMPs make them ideal candidates for commercial development. These peptides with widely varying compositions and sources share recurrent structural and functional features in mechanisms of action. Studying the mechanisms of AMP activity against bacteria may lead to the development of new antimicrobial agents that are more potent. Generally, AMPs are effective against bacteria by forming pores or disrupting membrane barriers. The important structural aspects of cytoplasmic membranes of pathogens and host cells will also be outlined to understand the selective antimicrobial actions. The antimicrobial activities of AMPs are related to multiple physicochemical properties, such as length, sequence, helicity, charge, hydrophobicity, amphipathicity, polar angle, and also self-association. These parameters are interrelated and need to be considered in combination. So, gathering the most relevant available information will help to design and choose the most effective AMPs.

Exploring the binding behavior mechanism of vitamin B12 to α-Casein and ß-Casein: multi-spectroscopy and molecular dynamic approaches.

The aim of this study was to investigate the behavior interaction of α-Casein-B12 and ß-Casein-B12 complexes as binary systems through the methods of multiple spectroscopic, zeta potential, calorimetric, and molecular dynamics (MD) simulation. Fluorescence spectroscopy denoted the role ofB12as a quencher in both cases of α-Casein and ß-Casein fluorescence intensities, which also verifies the existence of interactions. The quenching constants of α-Casein-B12 and ß-Casein-B12 complexes at 298 K in the first set of binding sites were 2.89 × 104 and 4.41 × 104 M-1, while the constants of second set of binding sites were 8.56 × 104 and 1.58 × 105 M-1, respectively. The data of synchronized fluorescence spectroscopy at Δλ = 60 nm were indicative of the closer location of ß-Casein-B12 complex to the Tyr residues. Additionally, the binding distance between B12 and the Trp residues of α-Casein and ß-Casein were obtained in accordance to the Förster's theory of nonradioactive energy transfer to be 1.95 nm and 1.85 nm, respectively. Relatively, the RLS results demonstrated the production of larger particles in both systems, while the outcomes of zeta potential confirmed the formation of α-Casein-B12 and ß-Casein-B12 complexes and approved the existence of electrostatic interactions. We also evaluated the thermodynamic parameters by considering the fluorescence data at three varying temperatures. According to the nonlinear Stern-Volmer plots of α-Casein and ß-Casein in the presence of B12 in binary systems, the two sets of binding sites indicated the detection of two types of interaction behaviors. Time-resolved fluorescence results revealed that the fluorescence quenching of complexes are static mechanism. Furthermore, the outcomes of circular dichroism (CD) represented the occurrence of conformational changes in α-Casein and ß-Casein upon their binding to B12 as the binary system. The experimental results that were obtained throughout the binding of α-Casein-B12 and ß-Casein-B12 complexes were confirmed by molecular modeling.Communicated by Ramaswamy H. Sarma.

Amino acid-mPEGs: Promising excipients to stabilize human growth hormone against aggregation.

Objectives: Today, the non-covalent PEGylation methods of protein pharmaceuticals attract more attention and possess several advantages over the covalent approach. In the present study, Amino Acid-mPEGs (aa-mPEGs) were synthesized, and the human Growth Hormone (hGH) stability profile was assessed in their presence and absence. Materials and Methods: aa-mPEGs were synthesized with different amino acids (Trp, Glu, Arg, Cys, and Leu) and molecular weights of polymers (2 and 5 KDa). The aa-mPEGs were analyzed with different methods. The physical and structural stabilities of hGH were analyzed by SEC and CD spectroscopy methods. Physical stability was assayed at different temperatures within certain intervals. Molecular dynamics (MD) simulation was used to realize the possible mode of interaction between protein and aa-mPEGs. The cell-based method was used to evaluate the cytotoxicity. Results: HNMR and FTIR spectroscopy indicated that aa-mPEGs were successfully synthesized. hGH as a control group is known to be stable at 4 °C; a pronounced change in monomer degradation is observed when stored at 25 °C and 37 °C. hGH:Glu-mPEG 2 kDa with a molar ratio of 1:1 to the protein solution can significantly increase the physical stability. The CD spectroscopy method showed that the secondary structure of the protein was preserved during storage. aa-mPEGs did not show any cytotoxicity activities. The results of MD simulations were in line with experimental results. Conclusion: This paper showed that aa-mPEGs are potent excipients in decreasing the aggregation of hGH. Glu-mPEG exhibited the best-stabilizing properties in a harsh environment among other aa-mPEGs.

Endogenous enzymatic antioxidant status of whiteleg shrimp (Litopenaeus vannamei) following exposure to sublethal concentrations of silver nanoparticles.

Immunotoxicity of silver nanoparticles (AgNPs) to whiteleg shrimp (Litopenaeus vannamei) was assessed using redox-status orchestrating enzymes. To this end, the shrimp was exposed to sublethal AgNPs concentrations (0 % LC50: control; 25 % LC50: 0.97 mg/L; 50 % LC50: 1.95 mg/L; 75 % LC50: 2.92 mg/L). During the experiment, the behavior of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GPx) was monitored, besides total antioxidant capacity (TAC) and malondialdehyde (MDA). The hepatopancreas SOD activity reduced about 63 %-76 % at.%50 LC50 and %75 LC50 AgNPs treatments, and CAT decreased in both tissues at 50 % LC50 AgNPs. TAC exhibited a U-form response in the hepatopancreas organ against stress caused by AgNPs, and hepatopancreas MDA displayed a time-dependent increase. Taken together, AgNPs triggered severe immunotoxicity through suppression of CAT, SOD, and TAC in the hepatopancreas tissue.

Discovery of New Ligand with Quinoline Scaffold as Potent Allosteric Inhibitor of HIV-1 and Its Copper Complexes as a Powerful Catalyst for the Synthesis of Chiral Benzimidazole Derivatives, and in Silico Anti-HIV-1 Studies.

In this paper, the novel Schiff base ligand containing quinoline moiety and its novel copper chelate complexes were successfully prepared. The catalytic activity of the final complex in the organic reaction such as synthesis of chiral benzimidazoles and anti-HIV-1 activity of Schiff base ligand and the products of this reaction were investigated. In addition, green chemistry reactions using microwaves, powerful catalyst synthesis, green recovery and reusability, and separation of products with economic, safe, and clean methods (green chemistry) are among the advantages of this protocol. The potency of these compounds as anti-HIV-1 agents was investigated using molecular docking into integrase (IN) enzyme with code 1QS4 and the GROMACS software for molecular dynamics simulation. The final steps were evaluated in case of RMSD, RMSF, and Rg. The results revealed that the compound VII exhibit a good binding affinity to integrase (Δg = -10.99 kcal/mol) during 100 ns simulation time, and the analysis of RMSD suggested that compound VII was stable in the binding site of integrase.

Multi spectroscopic and molecular simulation studies of propyl acridone binding to calf thymus DNA in the presence of electromagnetic force.

Introduction: Here, the interaction behavior between propyl acridones (PA) and calf thymus DNA (ct-DNA) has been investigated to attain the features of the binding behavior of PA with ct-DNA, which includes specific binding sites, modes, and constants. Furthermore, the effects of PA on the conformation of ct-DNA seem to be quite significant for comprehending the medicine's mechanism of action and pharmacokinetics. Methods: The project was accomplished through means of absorbance studies, fluorescence spectroscopy, circular dichroism, viscosity measurement, thermal melting, and molecular modeling techniques. Results: The intercalation of PA has been suggested by fluorescence quenching and viscosity measurements results while the thermal melting and circular dichroism studies have confirmed the thermal stabilization and conformational changes that seem to be associated with the binding. The binding constants of ct-DNA-PA complex, in the absence and presence of EMF, have been evaluated to be 6.19 × 104 M-1 and 2.95 × 104 M-1 at 298 K, respectively. In the absence of EMF, the ∆H0 and ∆S0 values that occur in the interaction process of PA with ct-DNA have been measured to be -11.81 kJ.mol-1 and 51.01 J.mol-1K-1, while in the presence of EMF they were observed to be -23.34 kJ.mol-1 and 7.49 J.mol-1K-1, respectively. These numbers indicate the involvement of multiple non-covalent interactions in the binding procedure. In a parallel study, DNA-PA interactions have been monitored by molecular dynamics simulations; their results have demonstrated DNA stability with increasing concentrations of PA, as well as calculated bindings of theoretical ΔG0. Conclusion: The complex formation between PA and ct-DNA has been investigated in the presence and absence of EMF through the multi spectroscopic techniques and MD simulation. These findings have been observed to be parallel to the results of KI and NaCl quenching studies, as well as the competitive displacement with EB and AO. According to thermodynamic parameters, electrostatic interactions stand as the main energy that binds PA to ct-DNA. Regarding the cases that involve the Tm of ct-DNA, EMF has proved to increase the stability of binding between PA and ct-DNA.

Understanding the binding behavior of Malathion with calf thymus DNA by spectroscopic, cell viability and molecular dynamics simulation techniques: binary and ternary systems comparison.

The interaction between calf thymus DNA (ctDNA) and Malathion in the absence and presence of Histone 1 has been enquired by the means of spectroscopic, viscometry, molecular modeling, and cell viability assay techniques. Malathion is capable of quenching the fluorescence of ct DNA in the absence and presence of H1. The binding constants of Malathion-ctDNA complex in the absence of H1 have been calculated to be 6.62 × 104, 4.31 × 104 and 1.93 × 104 M-1 at 298, 303, and 308 K, respectively that revealed static quenching in complex formation. The observed negative values of enthalpy and entropy changes indicate that the main binding interaction forces were van der Waals force and hydrogen bonding. The binding constant between Malathion and single-stranded ctDNA (ss ctDNA) seemed to be much weaker than that of Malathion and double-stranded ctDNA (ds ctDNA). Furthermore, Malathion can induce detectable alterations in the CD spectrum of ctDNA, along with changes in its viscosity. In the presence of H1, fluorescence quenching of ctDNA-Malathion complex displays dynamic behavior and binding constants were perceived to be 1.66 × 104, 2.93 × 104 and 5.77 × 104 M-1 at 298, 303, and 308 K, respectively. The different of interaction behavior between ctDNA and Malathion in the absence and presence of H1 clearly revealed H1 role in the complex formation and forces change between ctDNA and Malathion. The positive values of enthalpy and entropy changes have suggested that binding process is primarily driven by hydrophobic interactions. The tendency to interact with ss ctDNA, reduced viscosity have designated that the Malathion bound to ctDNA in the presence of H1 is groove binding. The results of molecular docking and molecular dynamics simulation also confirmed potent interactions between Malathion and the macromolecules in the binary and ternary systems.Communicated by Ramaswamy H. Sarma.

CB1 as a novel target for Ginkgo biloba's terpene trilactone for controlling chemotherapy-induced peripheral neuropathy (CIPN).

The application of antineoplastic chemotherapeutic agents causes a common side effect known as chemotherapy-induced peripheral neuropathy (CIPN) that leads to reducing the quality of patient's life. This research involves the performance of molecular docking and molecular dynamic (MD) simulation studies to explore the impact of terpenoids of Ginkgo biloba on the targets (CB-1, TLR4, FAAH-1, COX-1, COX-2) that can significantly affect the controlling of CIPN's symptoms. According to the in-vitro and in-vivo investigations, terpenoids, particularly ginkgolides B, A, and bilobalide, can cause significant effects on neuropathic pain. The molecular docking results disclosed the tendency of our ligands to interact with mainly CB1 and FAAH-1, as well as partly with TLR4, throughout their interactions with targets. Terpene trilactone can exhibit a lower rate of binding energy than CB1's inhibitor (7dy), while being precisely located in the CB1's active site and capable of inducing stable interactions by forming hydrogen bonds. The analyses of MD simulation proved that ginkgolide B was a more suitable activator and inhibitor for CB1 and TLR4, respectively, when compared to bilobalide and ginkgolide A. Moreover, bilobalide is capable of inhibiting FAAH-1 more effectively than the two other ligands. According to the analyses of ADME, every three ligands followed the Lipinski's rule of five. Considering these facts, the exertion of three ligands is recommended for their anti-inflammatory, neuroprotective, and anti-nociception influences caused by primarily activating CB1 and inhibiting FAAH-1 and TLR4; in this regard, these compounds can stand as potential candidates for the control and treatment of CIPN's symptoms.

COVID-19 Medical Research in Oman: A Bibliometric and Visualization Study.

Objectives: To study the quantum and pattern of the COVID-19-related medical research publications that had contributions from researchers in Oman, using bibliometric analysis. Methods: Data on the COVID-19-related medical research publications with contributions from authors in Oman were sourced from the Scopus database. The main search keywords were 'COVID-19' and 'Oman'. The search included data from 1 December 2019 till 21 August 2021. A bibliometric method utilizing citation analysis and science mapping was applied to the selected data. VOSviewer software was used for constructing and visualizing various bibliometric networks. Results: The search query returned 360 documents which included those by authors from Oman. After excluding 83 of these due to irrelevance, 277 documents were finally selected for analysis. Three macro research themes emerged: treatment of COVID-19 cases, epidemiology and impact of COVID-19, and etiology and clinical manifestations of COVID-19. A total of 4533 sources were cited in the selected 277 documents. Most articles were published in the International Journal of Infectious Diseases (IJID), followed by Oman Medical Journal, and Sultan Qaboos University Medical Journal. The most cited references included the Lancet, followed by the New England Journal of Medicine, and the Journal of the American Medical Association. The largest number of papers were authored by researchers from Sultan Qaboos University followed by the Oman Ministry of Health. Regarding the number of citations received per paper, the top rank went to the Ministry of Health, followed by Sultan Qaboos University Hospital and Khoula Hospital. Conclusions: Oman has significantly contributed to the COVID-19-related medical knowledge despite the challenges of conducting research amidst the increased workload during the pandemic. Most publications in Oman were collaborative projects. Based on the evaluated literature, further research focusing on vaccines and therapeutics is warranted.

1,2,3,4,6-Pentagalloyl glucose of Pistacia lentiscus can inhibit the replication and transcription processes and viral pathogenesis of SARS-COV-2.

SARS-COV-2 stands as the source of the most catastrophic pandemic of this century, known as COVID-19. In this regard, we explored the effects of five Pistacia sp. active ingredients on the most crucial targets of SARS-COV-2, including 3CLpro, PLpro, RdRp, helicase, NSP15, and E protein. The results of molecular docking determined 1,2,3,4,6-pentagalloyl glucose (PG) as the most effective compound of Pistacia sp, which also confirmed its excellent binding affinities and stable interactions with helicase (-10.76 kcal/mol), RdRp (-10.19 kcal/mol), E protein (-9.51 kcal/mol), and 3CLpro (-9.47 kcal/mol). Furthermore, MD simulation was conducted to investigate the stability of all complexes throughout a 100 ns. In contrast to PLpro and NSP15, the analyses of Lennard-Jones potential, RMSDas, PCA, and SASA verified the ability of PG in forming stable and adequate interactions with RdRp, helicase, 3CLpro, and E protein due to standing as an effective inhibitor among the six targets, these data proposed the capability of PG, the most important compound of Pistacia sp., in inducing antiviral, anti-inflammatory, and antioxidant impacts on RdRp, helicase, 3CLpro, and E protein. Therefore, the possibility of inhibiting the replication and transcription processes and viral pathogenesis of SARS-COV-2 may be facilitated through the application of PG.

LPTD: a novel linear programming-based topology determination method for cryo-EM maps.

SUMMARY: Topology determination is one of the most important intermediate steps toward building the atomic structure of proteins from their medium-resolution cryo-electron microscopy (cryo-EM) map. The main goal in the topology determination is to identify correct matches (i.e. assignment and direction) between secondary structure elements (SSEs) (α-helices and ß-sheets) detected in a protein sequence and cryo-EM density map. Despite many recent advances in molecular biology technologies, the problem remains a challenging issue. To overcome the problem, this article proposes a linear programming-based topology determination (LPTD) method to solve the secondary structure topology problem in three-dimensional geometrical space. Through modeling of the protein's sequence with the aid of extracting highly reliable features and a distance-based scoring function, the secondary structure matching problem is transformed into a complete weighted bipartite graph matching problem. Subsequently, an algorithm based on linear programming is developed as a decision-making strategy to extract the true topology (native topology) between all possible topologies. The proposed automatic framework is verified using 12 experimental and 15 simulated α-ß proteins. Results demonstrate that LPTD is highly efficient and extremely fast in such a way that for 77% of cases in the dataset, the native topology has been detected in the first rank topology in <2 s. Besides, this method is able to successfully handle large complex proteins with as many as 65 SSEs. Such a large number of SSEs have never been solved with current tools/methods. AVAILABILITY AND IMPLEMENTATION: The LPTD package (source code and data) is publicly available at https://github.com/B-Behkamal/LPTD. Moreover, two test samples as well as the instruction of utilizing the graphical user interface have been provided in the shared readme file. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Next-generation sequencing identified novel truncating mutations in BBS9 causing Bardet Biedl syndrome in two Iranian consanguineous families.

OBJECTIVES: Bardet-Biedl syndrome (BBS) is an autosomal recessive pleiotropic ciliopathy, which includes multi-organ clinical manifestations. The known genes involved in the development of the disease account for the causality in about 80% of the examined cases. MATERIALS & METHODS: We investigated two Iranian unrelated clinically diagnosed BBS patients, using a targeted next-generation sequencing panel consisting of 18 known BBS genes. The detected variants were investigated in the pedigree and studied using in silico tools for their pathogenicity. Patients' phenotypes were also assessed. RESULTS: Novel homozygous variants were detected in BBS9 gene in each patient, c.2014C>T, p.Gln672Ter and c.673_674insAA, p.Gln225GlnfsX10. The variants were segregated in the corresponding pedigree and were authenticated to obtain enough evidence to be categorized as pathogenic variants. CONCLUSION: Patients with truncating mutations in the same gene seem to show similar phenotypic features. Detection of novel and family-specific mutations is typically expected in the genetic hereditary diseases in Iran, which can finally lead to prevent the recurrence of the disease in the consanguineous marriages.

Evaluation of the binding effect and cytotoxicity assay of 2-Ethyl-5-(4-methylphenyl) pyramido pyrazole ophthalazine trione on calf thymus DNA: spectroscopic, calorimetric, and molecular dynamics approaches.

With advances in new drug therapies, it is essential to understand the interactions between drugs and target molecules. In this study, we applied multiple spectroscopic techniques including absorbance, fluorescence, circular dichroism spectroscopy, viscosity, thermal melting, calorimetric, and molecular dynamics (MD) simulation to study the interaction between 2-Ethyl-5-(4-methylphenyl) pyramido pyrazole ophthalazine trione (PPF) and calf thymus DNA (ct DNA) in the absence or presence of histone H1. PPF exhibits a high binding affinity towards ct DNA in binary and ternary systems. In addition, the result for the binding constant was observed within the range 104 M-1 achieved through fluorescence quenching data, while the values for enthalpy and entropy changes for ct DNA-PPF and (ct DNA-H1) PPF complexes were measured to be -72.54 kJ.mol-1 , -161.14 J.mol-1  K-1 , -85.34 kJ.mol-1 , and -19.023 J.mol-1  K-1 , respectively. Furthermore, in accordance with circular dichroism spectra, the inducement of ct DNA structural changes was observed during binding of PPF and H1 in binary and ternary system forms. The essential roles of hydrogen bonding and van der Waals forces throughout the interaction were suggested using thermodynamic parameters. According to the obtained data, the interaction mode of ct DNA-PPF and (ct DNA-H1) PPF complexes was intercalation binding. Suggested by the MD simulation study, the ct DNA-H1 complex caused a reduction in the stability of the DNA structure in the presence or absence of ligand, which demonstrated that PPF as an intercalating agent can further distort the structure. The information achieved from this study will be very helpful in understanding the effects of PPF on the conformational state of ct DNA in the absence or presence of the H1 molecule, which seems to be quite significant for clarifying the mechanisms of action and its pharmacokinetics.

A novel vision into the binding behavior of curcumin with human serum albumin-holo transferrin complex: molecular dynamic simulation and multi-spectroscopic perspectives.

In this work, we investigated the simultaneous binding of curcumin (CUR) to human serum albumin (HSA) and human-holo transferrin (HTF) in the roles of binary and ternary systems. The binding affinity and binding site of protein-protein interaction were studied by the methods of multiple spectroscopic and molecular dynamics (MD) simulation. According to the results, the measurements for binding constant of HSA-CUR, HTF-CUR and (HSA-HTF) CUR complexes were observed to be 1.51 × 105, 7.93 × 104 and 1.44 × 105 M-1 respectively. Thermodynamic parameters were considered to be set at three varying temperatures including 298, 303, and 308 K. In conformity to the negative values of ΔH0 and ΔS0 the significant roles of hydrogen binding and van der-Waals forces in the formation of complexes are quiet evident. The binding distance between Trp residues of HSA, HTF and HSA-HTF upon interaction with CUR, were acquired by applying the Förster's theory of non-radioactive energy transfer and reported to be 2.04 nm, 1.78 nm, and 1.86 nm, respectively. In accordance with the conductometry and Resonance light scattering (RLS) results, there were different interaction behaviors among the HSA-HTF complex and CUR in ternary system when being compared to the outcomes of binary system. The secondary structure of all three cases increased as the CUR concentration was intensified, which confirmed the inducement of proteins conformational changes through the application of circular dichroism (CD) technique. The experimental results that were acquired throughout the binding of HSA-CUR, HTF-CUR, and (HSA-HTF) CUR complexes were approved by molecular modeling.Communicated by Ramaswamy H. Sarma.

Three-Dimensional Graph Matching to Identify Secondary Structure Correspondence of Medium-Resolution Cryo-EM Density Maps.

Cryo-electron microscopy (cryo-EM) is a structural technique that has played a significant role in protein structure determination in recent years. Compared to the traditional methods of X-ray crystallography and NMR spectroscopy, cryo-EM is capable of producing images of much larger protein complexes. However, cryo-EM reconstructions are limited to medium-resolution (~4-10 Å) for some cases. At this resolution range, a cryo-EM density map can hardly be used to directly determine the structure of proteins at atomic level resolutions, or even at their amino acid residue backbones. At such a resolution, only the position and orientation of secondary structure elements (SSEs) such as α-helices and ß-sheets are observable. Consequently, finding the mapping of the secondary structures of the modeled structure (SSEs-A) to the cryo-EM map (SSEs-C) is one of the primary concerns in cryo-EM modeling. To address this issue, this study proposes a novel automatic computational method to identify SSEs correspondence in three-dimensional (3D) space. Initially, through a modeling of the target sequence with the aid of extracting highly reliable features from a generated 3D model and map, the SSEs matching problem is formulated as a 3D vector matching problem. Afterward, the 3D vector matching problem is transformed into a 3D graph matching problem. Finally, a similarity-based voting algorithm combined with the principle of least conflict (PLC) concept is developed to obtain the SSEs correspondence. To evaluate the accuracy of the method, a testing set of 25 experimental and simulated maps with a maximum of 65 SSEs is selected. Comparative studies are also conducted to demonstrate the superiority of the proposed method over some state-of-the-art techniques. The results demonstrate that the method is efficient, robust, and works well in the presence of errors in the predicted secondary structures of the cryo-EM images.

Whole-Exome Sequencing Identified a Novel Variant (C.405_422+39del) in DSP Gene in an Iranian Pedigree with Familial Dilated Cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) is a progressive heart condition characterized by left ventricular chamber enlargement associated with systolic heart failure and prolonged action potential duration. Genetic variations in genes that encode cytoskeleton, sarcomere, and nuclear envelope proteins are responsible for 45% of cases. In our study, we focused on a pedigree with familial DCM to decipher the potential genetic cause(s) in affected members developing arrhythmia, end-stage heart failure, and sudden death. METHODS: Whole-exome sequencing (WES) was exploited for a 27-year-old heart-transplanted female as the proband, and the derived data were filtered using the standard pipelines. RESULTS: A 57-nucleotide deletion (c.405_422+39del) in the desmoplakin gene (DSP) (NM_004415.4) was identified as a novel pathogenic variant. Familial segregation analysis indicated that this variant is present in clinically affected members and absent in unaffected members. CONCLUSION: It seems that the detected variant induces intron retention, resulting in a premature stop codon in intron 3 of DSP leading to production of a truncated, nonfunctional protein. Additionally, it can trigger a nonsense-mediated mRNA decay pathway associated with inhibition of protein production. The present study results illustrated that a novel deletion in DSP can cause DCM in an Iranian family.