Ligand-based pharmacophore mapping and virtual screening for identification of potential discoidin domain receptor 1 inhibitors

Abbreviations ADME absorption, distribution, metabolism, and excretion

MMGB/SA molecular mechanics generalized born surface area

IFD induced fit docking

RTK receptor tyrosine kinase

NSCLC non-small-cell lung cancer

ATP adenosine triphosphate

OPLS optimized potential for liquid stimulation

RMSD root mean square deviation

HTVS high-throughput virtual screening

SP standard precision

XP extra precision

OPLS-AA optimized potential for liquid stimulation-all atom

MD molecular simulation

MME molecular mechanics energies

SGB surface generalized born

POPC membrane 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine membrane

PDB Protein Data Bank

DDR1 discoidin domain receptor 1

DDR2 discoidin domain receptor 2

DDRs discoidin domain receptors

ECM extracellular matrix

TIP4P transferable intermolecular potential 4 point

NPT constant particle number, pressure and temperature

RMSF root mean square fluctuation

Communicated by Ramaswamy H. Sarma     

Effect of tea catechins on tRNA structure and dynamics

Abbreviations C catechin

ECG epicatechin gallate

EGCG Epigallocatechin gallate

A Adenine

C cytosine

G Guanine

U uracil

FTIR Fourier transform infrared

Communicated by Ramaswamy H. Sarma     

Vorinostat,a possible alternative to metronidazole for the treatment of amebiasis caused by Entamoeba histolytica

Abbreviations SAHA suberoylanilide hydroxamic acid

EhHDAC Histone Deacetylase from Entamoeba histolytica

Rg Radius of gyration

RMSD root-mean-square deviation

RMSF root-mean-square fluctuation

MDS molecular dynamics simulation

VMD Visual Molecular Dynamics

NAMD Nanoscale Molecular Dynamics

PBC periodic boundary conditions

PME Particle Mesh Ewald

3D three-dimensional

Cα alpha carbon

FDA Food and Drug Administration

ns nanoseconds

GPU CUDA Graphics Processing Unit Compute Unified Device Architecture

Communicated by Ramaswamy H. Sarma     

Rational MD simulations for improvement the affinity of nanobody against PlGF (placenta growth factor): mutagenesis based on electrostatic interactions

Abbreviations COM center of mass distance

MD molecular dynamics

MM-PBSA Molecular Mechanics Poisson–Boltzmann Surface Area

Nb nanobody

PlGF placenta growth factor

Rg radius of gyration

RMSD root mean-square deviation

SASA solvent-accessible surface area

VEGF vascular endothelial growth factor

     

Recent activities of the Microbiology in Schools Advisory Committee

Ecology and evolution

Agricultural education

Evolution and education

Education division elections

ISII in Europe

Tree project

Science teaching scholarship

Biology of terrestrial arthropods

A microscopied museum     

Molecular dynamics simulation studies on influenza A virus H5N1 complexed with sialic acid and fluorinated sialic acid

Abbreviations HA Hemagglutinin

MD Molecular Dynamics

MM-PBSA Molecular Mechanics Poisson–Boltzmann Surface Area

NA Neuraminidase

NAMD Nanoscale Molecular Dynamic Simulation

PMEMD Particle Mesh Ewald Molecular Dynamics

RMSD Root-Mean-Square Deviation

RMSF Root-Mean-Square Fluctuation

SIA sialic acid

VMD Visual Molecular Dynamics

Communicated by Ramaswamy H. Sarma     

Evolutionary significance and functional characterization of streptomycin adenylyltransferase from Serratia marcescens

Abstract

Complete functional annotations of proteins are essential to understand the role and mechanisms in pathogenesis. Aminoglycoside nucleotidyltransferases are the subclasses of aminoglycosides modifying enzymes conferring resistance to organisms. Insight into the structural and functional understanding of nucleotidyltransferase family protein provides vital information to combat pathogenesis. Phylogenetic analysis is employed to identify the evolutionary significance and common motif’s present among the homologs of nucleotidyltransferase family protein. Structure, sequence based approaches and molecular docking were implemented to predict the exact function of the protein. Wide distribution of the nucleotidyltransferase family protein in gram-positive and gram-negative organisms are evidenced from phylogenetic analysis. Five common motifs were present in all the homolog’s of nucleotidyltransferase family protein. Sequence-structure based functional annotations predicts that the targeted protein function as ATP-Mg dependent streptomycin adenylyltransferase. Structural comparisons and docking studies correlate well with the identified function. The complete function of nucleotidyltransferase family protein was identified as Streptomycin adenylyltransferase and it could be targeted as a potential therapeutic target to overcome antibiotic resistance.

Communicated by Ramaswamy H. Sarma

Abbreviations AAC aminoglycoside acetyltransferases

AME aminoglycoside modifying enzyme

ANT aminoglycoside nucleotidyltransferases

APH aminoglycoside phosphotransferases

ATP adenosine triphosphate

CASTp computer atlas and surface topography of proteins

DUF domains of unknown function

Glide grid-based ligand docking with energetic

HMM hidden Markov model

MAST motif alignment and search tool

MEGA molecular evolutionary genetics analysis

MEME multiple Em for motif elicitation

MSA multiple sequence alignment

NMP nucleoside monophosphate

NTP nucleoside triphosphate

NT nucleotidyltransferase

OPLS optimized potential for liquid simulation

XP extra precision

     

Modulation of p53 N-terminal transactivation domain 2 conformation ensemble and kinetics by phosphorylation

Abstract

Phosphorylation of protein is critical for various cell processes, which preferentially happens in intrinsically disordered proteins (IDPs). How phosphorylation modulates structural ensemble of disordered peptide remains largely unexplored. Here, using replica exchange molecular dynamics (REMD) and Markov state model (MSM), the conformational distribution and kinetics of p53 N-terminal transactivation domain (TAD) 2 as well as its dual-site phosphorylated form (pSer46, pThr55) were simulated. It reveals that the dual phosphorylation does not change overall size and secondary structure element fraction, while a change in the distribution of hydrogen bonds induces slightly more pre-existing bound helical conformations. MSM analysis indicates that the dual phosphorylation accelerates conformation exchange between disordered and order-like states in target-binding region. It suggests that p53 TAD2 after phosphorylation would be more apt to bind to both the human p62 pleckstrin homology (PH) domain and the yeast tfb1?PH domain through different binding mechanism, where experimentally it exhibits an extended and α-helix conformation, respectively, with increased binding strength in both complexes. Our study implies except binding interface, both conformation ensemble and kinetics should be considered for the effects of phosphorylation on IDPs. Abbreviations IDPs intrinsically disordered proteins

REMD replica exchange molecular dynamics

MSM Markov state model

TAD transactivation domain

PH pleckstrin homology

PRR proline-rich region

DBD DNA-binding domain

TET Tetramerization domain

REG regulatory domain

MD molecular dynamics

PME particle-mesh Ewald

TICA time-lagged independent component analysis

CK Chapman–Kolmogorov

GMRQ generalized matrix Rayleigh quotient

SARW self-avoiding random walk

KID kinase-inducible domain

MFPT mean first passage time

DSSP definition of secondary structure of proteins

RMSD root mean square deviation

R_g radius of gyration

R_ee end to end distance

Communicated by Ramaswamy H. Sarma     

Soft regions of protein surface are potent for stable dimer formation

Abstract

By having knowledge about the characteristics of protein interaction interfaces, we will be able to manipulate protein complexes for therapies. Dimer state is considered as the primary alphabet of the most proteins’ quaternary structure. The properties of binding interface between subunits and of noninterface region define the specificity and stability of the intended protein complex. Considering some topological properties and amino acids’ affinity for binding in interfaces of protein dimers, we construct the interface-specific recurrence plots. The data obtained from recurrence quantitative analysis, and accessibility-related metrics help us to classify the protein dimers into four distinct classes. Some mechanical properties of binding interfaces are computed for each predefined class of the dimers. The computed mechanical characteristics of binding patch region are compared with those of nonbinding region of proteins. Our observations indicate that the mechanical properties of protein binding sites have a decisive impact on determining the dimer stability. We introduce a new concept in analyzing protein structure by considering mechanical properties of protein structure. We conclude that the interface region between subunits of stable dimers is usually mechanically softer than the interface of unstable protein dimers. Abbreviations AAB average affinity for binding

ANM anisotropic network model

APC affinity propagation clustering

ASA accessible surface area

CCD inter residues distance

CSC complex stability code

DM distance matrix

ΔG_diss PISA-computed dissociation free energy

GNM Gaussian normal mode analysis

NMA normal mode analysis

PBP protein binding patch

PISA proteins, interfaces, structures and assemblies

rASA relative accessible area in respect to unfolded state of residues

RM recurrence matrix

rP relative protrusion

RP recurrence plot

RQA recurrence quantitative analysis

SEM standard error of mean

Communicated by Ramaswamy H. Sarma     

Chromosomes of African Hepatics—Jubulae

Abstract

The chromosome numbers of five species belonging to the Jubulae have been described, and are as follows:

Lejeuneaceae

Cololejeunea cf. dissita, n = 9.

Arehilejeunea autoiea Vanden Berghen, n=9.

Caudalejeunea hanningtonii (Mitt.) Schiffn., n =9.

Mastigolejeunea florea (Mitt.) Steph., n=9.

Frullaniaceae

Frullania spongiosa Steph., female, n = 9.

F. spongiosa Steph., male, n=8.

The author wishes to thank Dr E. W. Jones for assistance in identifications, especially with Cololejeunea cf. dissita.     

Structural dynamics behind variants in pyrazinamidase and pyrazinamide resistance

Abstract

Pyrazinamide (PZA) is an important component of first-line anti-tuberculosis (anti-TB) drugs. The anti-TB agent is activated into an active form, pyrazinoic acid (POA), by Mycobacterium tuberculosis (MTB) pncA gene encoding pyrazinamidase (PZase). The major cause of PZA-resistance has been associated with mutations in the pncA gene. We have detected several novel mutations including V131F, Q141P, R154T, A170P, and V180F (GeneBank Accession No. MH461111) in the pncA gene of PZA-resistant isolates during PZA drug susceptibility testing followed by pncA gene sequencing. Here, we investigated molecular mechanism of PZA-resistance by comparing the results of experimental and molecular dynamics. The mutants (MTs) and wild type (WT) PZase structures in apo and complex with PZA were subjected to molecular dynamic simulations (MD) at the 40?ns. Multiple factors, including root mean square deviations (RMSD), binding pocket, total energy, dynamic cross correlation, and root mean square fluctuations (RMSF) of MTs and WT were compared. The MTs attained a high deviation and fluctuation compared to WT. Binding pocket volumes of the MTs, were found, lower than the WT, and the docking scores were high than WT while shape complementarity scores were lower than that of the WT. Residual motion in MTs are seemed to be dominant in anti-correlated motion. Mutations at locations, V131F, Q141P, R154T, A170P, and V180F, might be involved in the structural changes, possibly affecting the catalytic property of PZase to convert PZA into POA. Our study provides useful information that will enhance the understanding for better management of TB. Abbreviations DST drug susceptibility testing

Δelec electrostatic energy

LJ Lowenstein–Jensen medium

MGIT mycobacterium growth indicator tubes

MTs mutants

MD molecular dynamic simulations

MTB Mycobacterium tuberculosis

NALC–NaOH N-acetyl-l-cysteine–sodium hydroxide

NIH National Institutes of Health

NPT amount of substance (N), pressure (P) temperature (T)

NVT moles (N), volume (V) temperature (T)

PZase pyrazinamidase

Δps polar solvation energy

PTRL Provincial Tuberculosis Reference Laboratory

RMSD root mean square deviations

RMSF root mean square fluctuations

ΔSASA solvent accessible surface area energy

TB tuberculosis

GTotal total binding free energy

ΔvdW Van der Waals energy

WT wild type

Communicated by Ramaswamy H. Sarma     

Virtual identification of novel PPARα/γ dual agonists by 3D-QSAR,molecule docking and molecular dynamics studies

Abstract

Peroxisome proliferator-activated receptors (PPARs) are considered important targets for the treatment of Type 2 diabetes (T2DM). To accelerate the discovery of PPAR α/γ dual agonists, the comparative molecular field analysis (CoMFA) were performed for PPARα and PPARγ, respectively. Based on the molecular alignment, highly predictive CoMFA model for PPARα was obtained with a cross-validated q² value of 0.741 and a conventional r² of 0.975 in the non-cross-validated partial least-squares (PLS) analysis, while the CoMFA model for PPARγ with a better predictive ability was shown with q² and r² values of 0.557 and 0.996, respectively. Contour maps derived from the 3D-QSAR models provided information on main factors towards the activity. Then, we carried out structural optimization and designed several new compounds to improve the predicted biological activity. To investigate the binding modes of the predicted compounds in the active site of PPARα/γ, a molecular docking simulation was carried out. Molecular dynamic (MD) simulations indicated that the predicted ligands were stable in the active site of PPARα/γ. Therefore, combination of the CoMFA and structure-based drug design results could be used for further structural alteration and synthesis and development of novel and potent dual agonists. Abbreviations DM diabetes mellitus

T2DM type 2 diabetes

PPARs peroxisome proliferator-activated receptors

LBDD ligand based drug design

3D-QSAR three-dimensional quantitative structure activity relationship

CoMFA comparative molecular field analysis

PLS partial least square

LOO leave-one-out

q² cross-validated correlation coefficient

ONC optimal number of principal components

r² non-cross-validated correlation coefficient

SEE standard error of estimate

F the Fischer ratio

r²_pred predictive correlation coefficient

DBD DNA binding domain

MD molecular dynamics

RMSD root-mean-square deviation

RMSF root mean square fluctuations

Communicated by Ramaswamy H. Sarma     

Site-specific metastasis formation

The metastatic spread of tumors is a well-coordinated process in which different types of

cancers tend to form metastases in defined organs. The formation of site-specific metastases

requires full compatibility between the intrinsic properties of the tumor cells and the tumor

microenvironment. It was recently found that chemokines which are expressed in specific loci

promote the adhesion, migration and invasion of tumor cells that express the corresponding

receptor/s. Of the different members of the family, the CXCL12 chemokine and its cognate

CXCR4 receptor are the prototypes of this process, although other members of the family (e.g.

CCR7 and CCR10) also play a role in determination of the metastatic spread. This commentary

addresses the fundamental roles of chemokines and their receptors in site-specific metastasis,

with emphasis on CXCL12-CXCR4. The article also describes some of the efforts that were

performed thus far in order to identify the intracellular components involved in this process. The

focus is put on the roles played by proteins that regulate adhesion and migration of tumor cells

in response to CXCL12, including mainly Focal Adhesion Kinase, Pyk2/RAFTK and members of

the Rho family of GTPases (RhoA, Rac, Cdc42). This is followed by discussion of open

questions that need to be addressed in future research, and of the potential therapeutic

implications of the findings that are available to date in this field.     

Inhibitory effects of persistent apoptotic cells on monoclonal antibody production in vitro

Cells undergoing apoptosis in vivo are rapidly detected and cleared by phagocytes. Swift

recognition and removal of apoptotic cells is important for normal tissue homeostasis

and failure in the underlying clearance mechanisms has pathological consequences

associated with inflammatory and auto-immune diseases. Cell cultures in vitro usually

lack the capacity for removal of non-viable cells because of the absence of phagocytes

and, as such, fail to emulate the healthy in vivo micro-environment from which dead cells

are absent. While a key objective in cell culture is to maintain viability at maximal levels,

cell death is unavoidable and non-viable cells frequently contaminate cultures in

significant numbers. Here we show that the presence of apoptotic cells in monoclonal

antibody-producing hybridoma cultures has markedly detrimental effects on antibody

productivity. Removal of apoptotic hybridoma cells by macrophages at the time of

seeding resulted in 100% improved antibody productivity that was, surprisingly to us,

most pronounced late on in the cultures. Furthermore, we were able to recapitulate this

effect using novel super-paramagnetic Dead-Cert?Nanoparticles to remove non-viable

cells simply and effectively at culture seeding. These results (1) provide direct evidence

that apoptotic cells have a profound influence on their non-phagocytic neighbours in

culture and (2) demonstrate the effectiveness of a simple dead-cell removal strategy for

improving antibody manufacture in vitro.     

Dodecamers derived from the crystal structure were found in the pre-crystallization solution of the transaminase from the thermophilic bacterium Thermobaculum terrenum by small-angle X-ray scattering

Abstract

The pre-crystallization solution of the transaminase from Thermobaculum terrenum (TaTT) has been studied by small-angle X-ray scattering (SAXS). Regular changes in the oligomeric composition of the protein were observed after the addition of the precipitant. Comparison of the observed oligomers with the crystal structure of TaTT (PDB ID 6GKR) shows that dodecamers may act as building blocks in the growth of transaminase single crystals. Correlating of these results to the similar X-ray studies of other proteins suggests that SAXS may be a valuable tool for searching optimum crystallization conditions. Abbreviation SAXS small-angle X-ray scattering

Ta transaminase

TaTT transaminase from Thermobaculum terrenum

PLP pyridoxal-5’-phosphate

R-PEA R-(þ)-1-phenylethylamine

BCAT branched-chain amino acid aminotransferase

DAAT D-aminoacid aminotransferase

R-TA R-amine:pyruvate transaminase

Communicated by Ramaswamy H. Sarma     

Complexation of cis-Pt and trans-Pt(NH3)2Cl2 with serum proteins: A potential application for drug delivery

Abbreviations HAS human serum albumin

BSA bovine serum albumin

β-LG beta-lactoglobulin

cis-Pt and trans-Pt Pt(NH₃)₂Cl₂

FTIR Fourier transform infrared

Communicated by Ramaswamy H. Sarma