Clodronic Acid has Strong Inhibitory Interactions with the Urease Enzyme of Helicobacter Pylori: Computer-aided Design and in vitro Confirmation.

BACKGROUND: Helicobacter Pylori (HP) infection could lead to various gastrointestinal diseases. Urease is the most important virulence factor of HP. It protects the bacterium against gastric acid. OBJECTIVE: Therefore, we aimed to design urease inhibitors as drugs against HP infection. METHODS: The DrugBank-approved library was assigned with 3D conformations and the structure of the urease was prepared. Using a re-docking strategy, the proper settings were determined for docking by PyRx and GOLD software. Virtual screening was performed to select the best inhibitory drugs based on binding affinity, FitnessScore, and binding orientation to critical amino acids of the active site. The best inhibitory drug was then evaluated by IC50 and the diameter of the zone of inhibition for bacterial growth. RESULTS: The structures of prepared drugs were screened against urease structure using the determined settings. Clodronic acid was determined to be the best-identified drug, due to higher PyRx binding energy, better GOLD FitnessScore, and interaction with critical amino acids of urease. In vitro results were also in line with the computational data. IC50 values of Clodronic acid and Acetohydroxamic Acid (AHA) were 29.78 ± 1.13 and 47.29 ± 2.06 µg/ml, respectively. Diameters of the zones of inhibition were 18 and 15 mm for Clodronic acid and AHA, respectively. CONCLUSION: Clodronic acid has better HP urease inhibition potential than AHA. Given its approved status, the development of a repurposed drug based on Clodronic acid would require less time and cost. Further, in vivo studies would unveil the efficacy of Clodronic acid as a urease inhibitor.

Proteome Exploration of Human Coronaviruses for Identifying Novel Vaccine Candidate: A Hierarchical Subtractive Genomics and Reverse Vaccinology Approach.

BACKGROUND: The SARS-CoV-2 has been responsible for infecting more than 613,615,658 people in 222 countries by September 11, 2022, of which 6,516,076 have died. COVID-19 was introduced by World Health Organization as a global concern and a pandemic disease due to its prevalence. OBJECTIVE: Developing preventive or therapeutic medications against 2019-nCoV is an urgent need, and has been deemed as a high priority among scientific societies; in this regard, the production of effective vaccines is one of the most significant and high-priority requirements. Because of costly and time-consuming process of vaccine design, different immunoinformatics methods have been developed. METHODS: At the beginning of vaccine design, the proteome study is essential. In this investigation, the whole human coronavirus proteome was evaluated using the proteome subtraction strategy. Out of 5945 human coronavirus proteins, five new antigenic proteins were selected by analyzing the hierarchical proteome subtraction, and then their various physicochemical and immunological properties were investigated bioinformatically. RESULTS: All five protein sequences are antigenic and non-allergenic proteins; moreover, the spike protein group, including spike glycoprotein (E2) (Peplomer protein), spike fragment and spike glycoprotein fragment, showed acceptable stability, which can be used to design new vaccines against human coronaviruses. CONCLUSION: The selected peptides and the other proteins introduced in this study (HE, orf7a, SARS_X4 domain-containing protein and protein 8) can be employed as a suitable candidate for developing a novel prophylactic or therapeutic vaccine against human coronaviruses.

Interaction of indole-3-acetic acid with horseradish peroxidase as a potential anticancer agent: from docking to molecular dynamics simulation.

The oxidation process, catalyzed by the peroxidase enzymes, occurs in all domains of life to detoxify the hydrogen peroxide toxicity. The most well-known, applicable and vastly studied member of the peroxidases family is horseradish peroxidase (HRP), especially the isoenzyme C (HRP C). HRP (primarily HRP C) is commercially available and applicable in biotechnology and diagnosis. Recently, a novel application of HRP has been introduced in cancer therapy as the combination of HRP with indole-3-acetic acid (IAA). The anticancer activity of HRP/IAA complex is through oxidation of IAA by HRP in hypoxic tumor condition, which leads to apoptosis and cancerous cell death. However, the molecular interaction of HRP/IAA has not been elucidated. Identifying the interaction of IAA with HRP would provide a better insight into its function and applications. In this study, molecular docking and molecular dynamics (MD) simulation were applied to determine the molecular interaction of the IAA/HRP complex. The docking study represented that IAA bound at the 'exposed' heme edge of the HRP enzyme, and the IAA entrance to the enzyme was situated at the carboxymethyl side-chain of the selected structure. Our computational results showed the HRP/IAA complex structure stability. While hydrogen bond formation with ARG38 and HIS42 stabilized the substrate, hydrophobic interactions with Phe68, Gly69, Leu138, Pro139, Pro141 and Phe179 contributed to IAA/HRP complex stability. The results can help to better understand peroxidase enzyme activity and would pave the way for future development of new therapeutics with improved anticancer efficacy.Communicated by Ramaswamy H. Sarma.

Exploring the dysregulated mRNAs-miRNAs-lncRNAs interactions associated to idiopathic non-obstructive azoospermia.

Non-obstructive azoospermia (NOA) is the most clinical problem in case of infertility. About 70% of NOA patients are idiopathic with uncharacterized molecular mechanisms. This study aimed to analyze the possible pathogenic miRNA-target gene interaction and lncRNA-miRNA association involved in NOA. In the current study, differentially expressed (DE) nRNAs, miRNAs and lncRNAs were determined using the microarray dataset and statistical software R. miRNAs-mRNA and miRNA-lncRNA interactions were identified and the base-pair binding between the seed region of miRNAs and complementary nucleotides in 3' UTR of mRNAs were analyzed. The influence of the validated single nucleotide polymorphisms (SNPs) was described by calculating the minimum free energy (MFE) of the interaction. A total of 74 mRNAs, 14 miRNAs, and 10 lncRNAs were identified to have significant differential expression in testicular tissue between patients and the fertile group. Four of the DE-mRNAs and all of the reported DE-miRNAs were upregulated. In addition, all of the represented DE-lncRNAs were showed to be downregulated. miR-509-5p and miR-27b-3p were found to interact with target gene polo-like kinase 1 (PLK1) and Cysteine-rich secretory protein2 (CRISP2), respectively. Rs550967205 (A > G) positioned at 3' UTR CRISP2 and rs544604911 (T > C) located at 3' UTR PLK1, with lowest MFE in miRNA-mRNA interaction, were assumed to have possible pathogenic roles linked to spermatogenesis arrest. The results of the study provide new clues to understand the regulatory roles of miRNAs and lncRNAs in the pathogenesis and diagnosis of idiopathic azoospermia. Communicated by Ramaswamy H. Sarma.

Pierce into Structural Changes of Interactions Between Mutated Spike Glycoproteins and ACE2 to Evaluate Its Potential Biological and Therapeutic Consequences.

The structural consequences of ongoing mutations on the SARS-CoV-2 spike-protein remains to be fully elucidated. These mutations could change the binding affinity between the virus and its target cell. Moreover, obtaining new mutations would also change the therapeutic efficacy of the designed drug candidates. To evaluate these consequences, 3D structure of a mutant spike protein was predicted and checked for stability, cavity sites, and residue depth. The docking analyses were performed between the 3D model of the mutated spike protein and the ACE2 protein and an engineered therapeutic ACE2 against COVID-19. The obtained results revealed that the N501Y substitution has altered the interaction orientation, augmented the number of interface bonds, and increased the affinity against the ACE2. On the other hand, the P681H mutation contributed to the increased cavity size and relatively higher residue depth. The binding affinity between the engineered therapeutic ACE2 and the mutant spike was significantly higher with a distinguished binding orientation. It could be concluded that the mutant spike protein increased the affinity, preserved the location, changed the orientation, and altered the interface amino acids of its interaction with both the ACE2 and its therapeutic engineered version. The obtained results corroborate the more aggressive nature of mutated SARS-CoV-2 due to their higher binding affinity. Moreover, designed ACe2-baased therapeutics would be still highly effective against covid-19, which could be the result of conserved nature of cellular ACE2. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10989-021-10346-1.

Hotspots for mutations in the SARS-CoV-2 spike glycoprotein: a correspondence analysis.

Spike glycoprotein (Sgp) is liable for binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to the host receptors. Since Sgp is the main target for vaccine and drug designing, elucidating its mutation pattern could help in this regard. This study is aimed at investigating the correspondence of specific residues to the SgpSARS-CoV-2 functionality by explorative interpretation of sequence alignments. Centrality analysis of the Sgp dissects the importance of these residues in the interaction network of the RBD-ACE2 (receptor-binding domain) complex and furin cleavage site. Correspondence of RBD to threonine500 and asparagine501 and furin cleavage site to glutamine675, glutamine677, threonine678, and alanine684 was observed; all residues are exactly located at the interaction interfaces. The harmonious location of residues dictates the RBD binding property and the flexibility, hydrophobicity, and accessibility of the furin cleavage site. These species-specific residues can be assumed as real targets of evolution, while other substitutions tend to support them. Moreover, all these residues are parts of experimentally identified epitopes. Therefore, their substitution may affect vaccine efficacy. Higher rate of RBD maintenance than furin cleavage site was predicted. The accumulation of substitutions reinforces the probability of the multi-host circulation of the virus and emphasizes the enduring evolutionary events.

Design of a multi-epitope protein vaccine against herpes simplex virus, human papillomavirus and Chlamydia trachomatis as the main causes of sexually transmitted diseases.

Sexually transmitted diseases (STDs) have a profound effect on reproductivity and sexual health worldwide. According to world health organization (WHO) 375 million new case of STD, including chlamydia trachomatis (chlamydia), Neisseria gonorrhoeae, HSV, HPV has been reported in 2016. More than 30 diverse pathogenesis have identified to be transmitted through sexual intercourse. Of these, viral infections (hepatitis B, herpes simplex virus (HSV or herpes), HIV, and human papillomavirus (HPV) are incurable. However, symptoms caused by the incurable viral infections can be alleviated through treatment. Antimicrobial resistance (AMR) of sexually transmitted infections (STIs) to antibiotics has increased recent years, in this regard, vaccination is proposed as an important strategy for prevention or treatment of STDs. Vaccine against HPV 16 and 18 suggests a new approach for controlling STDs but until now, there is no prophylactic or therapeutic vaccine have been approved for HSV-2 and Chlamydia trachomatis (CT); in this reason, developing an efficient vaccine is inevitable. Recently, different combinatorial forms of subunit vaccines against two or three type of bacteria have been designed. In this study, to design a combinatorial vaccine against HSV, CT, and HPV, the E7 and L2 from HPV, glycoprotein D from HSV-2 and ompA from CT were selected as final antigens. Afterward, the immunodominant helper T lymphocytes (HTLs) and cytolytic T lymphocytes (CTLs) epitopes were chosen from aforesaid antigens. P30 (tetanus toxoid epitope) as universal T-helper were also added to the vaccine. Moreover, flagellin D1/D0 as TLR5 agonist and the RS09 as a TLR4 ligand were incorporated to N and C-terminals of peptide vaccine, respectively. Finally, all selected parts were fused together by appropriate linkers to enhance vaccine efficiency. The physicochemical, structural, and immunological properties of the designed vaccine protein were assessed. To achieve the best 3D model of the protein vaccine, modeling, refinement, and validation of modeled structures were also done. Docking evaluation demonstrated suitable interaction between the vaccine and TLR5. Moreover, molecular dynamics (MD) studies showed an appropriate and stable structure of protein and TLR5. Based on immunoinformatic analysis, our vaccine candidate could potentially incite humoral and cellular immunities, which are critical for protection against HPV, HSV-2, and chlamydia trachomatis. It should be noted that, experimental studies are needed to confirm the efficacy of the designed vaccine.

In silico Approaches for the Design and Optimization of Interfering Peptides Against Protein-Protein Interactions.

Large contact surfaces of protein-protein interactions (PPIs) remain to be an ongoing issue in the discovery and design of small molecule modulators. Peptides are intrinsically capable of exploring larger surfaces, stable, and bioavailable, and therefore bear a high therapeutic value in the treatment of various diseases, including cancer, infectious diseases, and neurodegenerative diseases. Given these promising properties, a long way has been covered in the field of targeting PPIs via peptide design strategies. In silico tools have recently become an inevitable approach for the design and optimization of these interfering peptides. Various algorithms have been developed to scrutinize the PPI interfaces. Moreover, different databases and software tools have been created to predict the peptide structures and their interactions with target protein complexes. High-throughput screening of large peptide libraries against PPIs; "hotspot" identification; structure-based and off-structure approaches of peptide design; 3D peptide modeling; peptide optimization strategies like cyclization; and peptide binding energy evaluation are among the capabilities of in silico tools. In the present study, the most recent advances in the field of in silico approaches for the design of interfering peptides against PPIs will be reviewed. The future perspective of the field and its advantages and limitations will also be pinpointed.

Non-adaptive Evolution of Trimeric Autotransporters in Brucellaceae.

Brucella species are Gram-negative, facultative intracellular pathogens. They are the main cause of brucellosis, which has led to a global health burden. Adherence of the pathogen to the host cells is the first step in the infection process. The bacteria can adhere to various biotic and abiotic surfaces using their outer membrane proteins. Trimeric autotransporter adhesins (TAAs) are modular homotrimers of various length and domain complexity. They are a diverse, and widespread gene family constituting the type Vc secretion pathway. These adhesins have been established as virulence factors in Brucellaceae. To date, no comprehensive and exhaustive study has been performed on the trimeric autotransporter family in the genus. In the present study, various bioinformatics tools were used to provide a novel evolutionary insight into the sequence and structure of this protein family in Brucellaceae. To this end, a dataset of all trimeric autotransporters from the Brucella genomes was built. Analyses included but were not limited to sequence alignment, phylogenetic tree constructions, codon-based test for selection, clustering of the sequences, and structure (primary to quaternary) predictions. Batch analyzes of the dataset suggested the existence of a few structural domains within the whole population. BatA from the B. abortus 2308 genome was selected as a reference to describe the features of these structural domains. Furthermore, we examined the structural basis for the observed rigidity and resiliency of the protein structure through a molecular dynamics evaluation, which led us to deduce that the random drift results in the non-adaptive evolution of the trimeric autotransporter genes in the Brucella genus. Notably, the modifications have occurred across the genus without interference of gene transmission.

Amino Acids Sequence-based Analysis of Arginine Deiminase from Different Prokaryotic Organisms: An In Silico Approach.

BACKGROUND: Arginine deiminase is a bacterial enzyme, which degrades L-arginine. Some human cancers such as hepatocellular carcinoma (HCC) and melanoma are auxotrophic for arginine. Therefore, PEGylated arginine deiminase (ADI-PEG20) is a good anticancer candidate with antitumor effects. It causes local depletion of L-arginine and growth inhibition in arginineauxotrophic tumor cells. The FDA and EMA have granted orphan status to this drug. Some recently published patents have dealt with this enzyme or its PEGylated form. OBJECTIVE: Due to increasing attention to it, we aimed to evaluate and compare 30 arginine deiminase proteins from different bacterial species through in silico analysis. METHODS: The exploited analyses included the investigation of physicochemical properties, multiple sequence alignment (MSA), motif, superfamily, phylogenetic and 3D comparative analyses of arginine deiminase proteins thorough various bioinformatics tools. RESULTS: The most abundant amino acid in the arginine deiminase proteins is leucine (10.13%) while the least amino acid ratio is cysteine (0.98%). Multiple sequence alignment showed 47 conserved patterns between 30 arginine deiminase amino acid sequences. The results of sequence homology among 30 different groups of arginine deiminase enzymes revealed that all the studied sequences located in amidinotransferase superfamily. Based on the phylogenetic analysis, two major clusters were identified. Considering the results of various in silico studies; we selected the five best candidates for further investigations. The 3D structures of the best five arginine deiminase proteins were generated by the I-TASSER server and PyMOL. The RAMPAGE analysis revealed that 81.4%-91.4%, of the selected sequences, were located in the favored region of arginine deiminase proteins. CONCLUSION: The results of this study shed light on the basic physicochemical properties of thirty major arginine deiminase sequences. The obtained data could be employed for further in vivo and clinical studies and also for developing the related therapeutic enzymes.

Trimeric autotransporter adhesins in Acinetobacter baumannii, coincidental evolution at work.

Trimeric autotransporter (TAA), also known as type Vc secretion system, is expressed by many strains of Acinetobacter baumannii, an opportunistic pathogen, which is responsible for nosocomial infections worldwide. TAAs, are modular homotrimeric virulence factors, containing a signal peptide, complex stalk, and conserved membrane anchoring domain. The evolutionary mechanisms underlying the evolvement of these adhesins are not clear. Here, we showed that TAA genes were laterally acquired and underwent gene duplication and recombination. The heterogeneity of TAA nucleotide sequences, GC content, codon usage, and the probability of recombination and duplication events were assessed by MEGA7. Given the heterogeneity of sequences, we used all-against-all BLAST for clustering the TAAs. The pattern of distribution of TAAs are highly scattered; GC content and codon usage for these genes are variable. Multiple events of lateral gene transfer from the early history of Acinetobacter and the occurrence of gene duplication, gene loss, and recombination after acquiring the alien genes may explain the scattered pattern of distribution of TAAs. Additionally, this gene is not present in many clinical isolates of A. baumannii, thus is not a single virulence factor attributing to the infection. The advantage of harboring such genes might be adopting to different environments by developing the biofilm communities. We suggested that TAA genes were laterally acquired in the environmental context and incidentally provided some benefits at the infection site. Thus, coincidental evolution theory may be better suited for describing the evolution of TAA genes in A. baumannii genomes.

In silico Analysis of Different Signal Peptides for Secretory Production of Arginine Deiminase in Escherichia coli.

BACKGROUND: Secretory production of recombinant protein in bacterial hosts fulfills several advantages. Selecting an appropriate secretory signal peptide is a critical step in secretory production of different protein. Several patents report the usage of signal peptides for secretory production of recombinant proteins in E. coli. In silico identification of suitable signal peptides is a reliable and cost-effective alternative to experimental approaches. OBJECTIVE: This study was aimed to predict best signal peptides for the secretory production of recombinant arginine deiminase in E. coli. METHODS: In this study, 30 different signal peptide sequences were retrieved from database. The signal peptide probability, location of cleavage sites, and n, h and c regions were predicted by SignalP 4.1 and Phobius servers. After purging the 30 predicted secretory signal peptides, TorT, bla, NrfA, TolB, PapC, PldA, Lpp were removed. Several physicochemical properties of the remaining potential SPs were determined by ProtParam, PROSO II, and SOLpro servers for theoretically selecting the best candidates. RESULTS AND CONCLUSION: Based on physicochemical properties, the signal peptides of OmpC, OmpF, and DsbA were identified respectively as the promising candidates for efficient secretory production of arginine deiminase in E. coli. Although the computational approach has established itself as a basis of modern biotechnology, the experimental study is necessary to validate its results. The criteria used in this study could be applied to other targets for recombination processes.

Decreasing the immunogenicity of arginine deiminase enzyme via structure-based computational analysis.

The clinical applications of therapeutic enzymes are often limited due to their immunogenicity. B-cell epitope removal is an effective approach to solve this obstacle. The identification of hot spot epitopic residues is a critical step in the removal of protein B-cell epitope. Hereof, computational approaches are a suitable alternative to costly and labor-intensive experimental approaches. Arginine deiminase, a Mycoplasma arginine-catabolizing enzyme, is in the clinical trial for treating arginine auxotrophic cancers, especially hepatocellular carcinomas and melanomas through depleting plasma arginine and causing cell starvation. In this study, arginine deiminase from Mycoplasma hominis (MhADI) was computationally analyzed for recognizing and locating its immune-reactive regions. The 3D structure of the bioactive form of MhADI was modeled. The B-cell epitope mapping of protein was performed using various servers with different algorithms. Six segments: 31-40, 48-55, 131-140, 196-206, 294-314, and 331-344 were predicted to be the consensus immunogenic regions. The modification of epitopic hot spot residue was performed to reduce immune-reactiveness. The hot spot residue was selected considering a high B-cell epitope score, convexity index, surface accessibility, flexibility, and hydrophilicity. The structure stability of native and mutant proteins was evaluated through molecular dynamics simulation. The E304L mutein was suggested as a lower antigenic and stable enzyme derivative.

Exploring dengue proteome to design an effective epitope-based vaccine against dengue virus.

Dengue, a mosquito-borne disease, is caused by four known dengue serotypes. This infection causes a range of symptoms from a mild fever to a sever homorganic fever and death. It is a serious public health problem in subtropical and tropical countries. There is no specific vaccine currently available for clinical use and study on this issue is ongoing. In this study, bioinformatics approaches were used to predict antigenic, immunogenic, non-allergenic, and conserved B and T-cell epitopes as promising targets to design an effective peptide-based vaccine against dengue virus. Molecular docking analysis indicated the deep binding of the identified epitopes in the binding groove of the most popular human MHC I allele (human leukocyte antigens [HLA] A*0201). The final vaccine construct was created by conjugating the B and T-cell identified epitopes using proper linkers and adding an appropriate adjuvant at the N-terminal. The characteristics of the new subunit vaccine demonstrated that the epitope-based vaccine was antigenic, non-toxic, stable, and soluble. Other physicochemical properties of the new designed construct including isoelectric point value, aliphatic index, and grand average of hydropathicity were biologically considerable. Molecular docking of the engineered vaccine with Toll-like receptor 2 (TLR2) model revealed the hydrophobic interaction between the adjuvant and the ligand binding regions in the hydrophobic channel of TLR2. The study results indicated the high potential capability of the new multi-epitope vaccine to induce cellular and humoral immune responses against the dengue virus. Further experimental tests are required to investigate the immune protection capacity of the new vaccine construct in animal models. Communicated by Ramaswamy H. Sarma.

Arginine Deiminase: Current Understanding and Applications.

BACKGROUND: Arginine deiminase (ADI), an arginine catabolizing enzyme, is considered as an anti-tumor agent for the treatment of arginine auxotrophic cancers. However, some obstacles limit its clinical applications. OBJECTIVE: This review will summarize the clinical applications of ADI, from a brief history to its limitations, and will discuss the different ways to deal with the clinical limitations. METHOD: The structure analysis, cloning, expression, protein engineering and applications of arginine deiminase enzyme have been explained in this review. CONCLUSION: Recent patents on ADI are related to ADI engineering to increase its efficacy for clinical application. The intracellular delivery of ADI and combination therapy seem to be the future strategies in the treatment of arginine auxotrophic cancers. Applying ADIs with optimum features from different sources and or ADI engineering, are promising strategies to improve the clinical application of ADI.

Medium Optimization for Recombinant Soluble Arginine Deiminase Expression in Escherichia coli Using Response Surface Methodology.

OBJECTIVE: Optimization of the medium for recombinant arginine deiminase production in E. coli was performed using response surface methodology. This is the first study of optimization of recombinant arginine deiminase production in E. coli by the use of response surface methodology. METHODS: A Mycoplasm arginine deiminase gene was computationally optimized and inserted into pET-3a (+) expression vector. The synthetic pET3a-arginine deiminase construct was cloned and overexpressed in E. coli. The effect of glucose, NH4Cl and MgSO4.7H2O concentrations on the expression of intracellular soluble arginine deiminase was investigated using central composite design (CCD). RESULTS: The maximum arginine deiminase activity (U/mL) was obtained in optimal concentrations g/L of glucose, 6.6; NH4Cl, 1.81; MgSO4.7H2O, 0.94; KH2PO4, 3.0; Na2HPO4, 6.78; NaCl, 0.5; CaCl2, 0.1 mL/L (1M), which was about 6.6 fold higher than that in M9 standard medium. CONCLUSION: The obtained result can be utilized for large-scale production of this enzyme and related recombinant protein.

Suicide epidemiology and characteristics among young Iranians at poison ward, Loghman-Hakim Hospital (1997-2007).

BACKGROUND: Suicide is a critical public health problem. In developing countries, the highest suicide rate is found in young adults with remarkable increasing rate. In this study, we have evaluated the epidemiology and characteristics of 8-16-year-old individuals who attempted suicideand were hospitalized in Loghman-Hakim Hospital, Tehran, Iran from 1997 to 2007. METHODS: A total of 6414 hospitalized patients, ages 8-16, who attempted suicide and were residents of Loghman-Hakim Hospital were investigated. We performed a retrospective chart review to study the characteristics of cases in a 10-year period by review of psychiatric and medical records. RESULTS: Out of 6414 patients, 22.6% were males, 5978 patients were 12-16 years old and the rest were aged 8-12 years. During the 10-year period, suicides showed a rising trend among adults, while in children no significant increase was detected. Communicative disorders were the most common underlying risk factors, particularly in females. One patient out of five cases had psychiatric disorders, of which adjustment disorders were the most predominant. A remarkable peak in suicides was observed in May and July, while winter had the highest suicide rate among seasons. CONCLUSIONS: Suicide due to drug overdose is higher in females than males in young population. This increasing trend is a psychiatric concern and should be resolved by improving mental and public health.

Molecular dynamics simulation study of the interaction of Piscidin 1 with DPPC bilayers: structure-activity relationship.

To study structure-activity relationship of antimicrobial peptides and to design novel antimicrobial peptides with selectivity for bacterial cells, we have performed molecular dynamics simulations of the interaction of Piscidin (Pis1) and its two analogues (Pis1-AA and Pis1-PG) with dipalmitoylphosphatidylcholine (DPPC) bilayer through 45 ns. Our results inform us of the detailed location and orientation of the peptide with respect to the bilayer as well as provide about hydrogen-bond-formation patterns and electrostatics interactions. Simulations show that Pis1 and Pis-AA form the most hydrogen bonds and Pis-PG forms the fewest hydrogen bonds with lipid. Thus, Pis1 and Pis-AA should have stronger interactions with the lipid head group when compared to Pis-PG. Experimental studies have shown that Pis1 and Pis1-AA have a high antimicrobial and hemolytic activities, and Pis1-PG has low hemolytic activity while keeps potent antimicrobial activity. Our results complement the previous experimental studies. According to our MD results and previous experimental studies, Pis1 and Pis1-AA are more effective at the zwitterionic bilayer comparing Pis1-PG. These properties of Pis1-PG could be accordance with its low hemolytic activities.