RND family proteins are transmembrane proteins identified as large spectrum drug transporters involved in multi‐drug resistance. A prototypical case in this superfamily, responsible for antibiotic resistance in selected gram negative bacteria, is AcrB. AcrB forms a trimer using the proton motive force to efflux drugs, implementing a functional rotation mechanism. Unfortunately, the size of the system

Hydrophobic association is the key contributor behind the formation of well packed core of a protein which is often believed to be an important step for folding from an unfolded chain to its compact functional form. While most of the protein folding/unfolding studies have evaluated the changes in the hydrophobic interactions during chemical denaturation, the role of hydrophilic amino acids in such

Lyme disease is the most widespread vector‐transmitted disease in North America and Europe, caused by infection with Borrelia burgdorferi sensu lato complex spirochetes. We report the solution NMR structure of the B. burgdorferi outer surface lipoprotein BBP28, a member of the multicopy lipoprotein (mlp) family. The structure comprises a tether peptide, five α‐helices and an extended C‐terminal loop

We present a novel Java‐based program denominated PeptiDesCalculator for computing peptide descriptors. These descriptors include: redefinitions of known protein parameters to suite the peptide domain, generalization schemes for the global descriptions of peptide characteristics, as well as empirical descriptors based on experimental evidence on peptide stability and interaction propensity. The PeptiDesCalculator

A major challenge for protein databases is reconciling information from diverse sources. This is especially difficult when some information consists of secondary, human‐interpreted rather than primary data. For example, the Swiss‐Prot database contains curated annotations of subcellular location that are based on predictions from protein sequence, statements in scientific articles, and published experimental

Signal peptides help newly synthesized proteins reach the cell membrane or be secreted. As part of a biological process key to immune response and surveillance in humans, and associated with diseases, e.g. Alzheimer, remnant signal peptides and other transmembrane segments are proteolyzed by the intramembrane aspartyl protease (IAP) enzyme family. Here, we identified IAP orthologs throughout the tree

Accurate prediction of protein secondary structure (alpha‐helix, beta‐strand and coil) is a crucial step for protein inter‐residue contact prediction and ab initio tertiary structure prediction. In a previous study, we developed a deep belief network‐based protein secondary structure method (DNSS1) and successfully advanced the prediction accuracy beyond 80%. In this work, we developed multiple advanced

Human interleukin‐6 (hIL‐6) is a multifunctional cytokine that regulates immune and inflammatory responses in addition to metabolic and regenerative processes and cancer. hIL‐6 binding to the IL‐6 receptor (IL‐6Rα) induces homodimerization and recruitment of the glycoprotein (gp130) to form a hexameric signaling complex. Anti‐IL‐6 and IL‐6R antibodies are clinically approved inhibitors of IL‐6 signaling

N‐acetylglucosamine 6‐phosphate deacetylase (NagA) catalyzes the conversion of N‐acetylglucosamine‐6‐phosphate to glucosamine‐6‐phosphate in amino sugar catabolism. This conversion is an essential step in the catabolism of sialic acid in several pathogenic bacteria, including Pasteurella multocida, and thus NagA is identified as a potential drug target. Here, we report the unique structural features

Flexible regions in proteins, such as loops, cannot be represented by a single conformation. Instead, conformational ensembles are needed to provide a more global picture. In this context, identifying statistically meaningful conformations within an ensemble generated by loop sampling techniques remains an open problem. The difficulty is primarily related to the lack of structural data about these

Enhanced intracellular survival (Eis) proteins belonging to the superfamily of the GCN5‐related N‐acetyltransferases play important functions in mycobacterial pathogenesis. In Mycobacterium tuberculosis, Eis enhances the intracellular survival of the bacilli in macrophages by modulating the host immune response and is capable to chemically modify and inactivate aminoglycosides. In nontuberculous mycobacteria

Biosimilars offer an avenue for potential cost savings and enhanced patient access to various emerging therapies in a budget neutral way. Biosimilars of the granulocyte colony stimulating factor (GCSF) are an excellent example in this regard with as many as 18 versions of the drug being currently approved across globe for treatment of neutropenia. Here, we identified oxidation of the various methionine

With the development of various nanomaterial expected to be used in biomedical fields, it is more important to evaluate and understand their potential effects on biological system. In this work, two proteins with different structure, Villin Headpiece (HP35) with α‐helix structure and protofibrils Aβ1‐42 with five β‐strand chains, were selected and their interactions with silicene were studied by means

Activation of T cells triggers the expression of regulatory molecules like the programmed cell death 1 (PD1) protein. The association of PD1 with the natural ligands PDL1 and PDL2 induces an inhibitory signal that prevents T cells from proliferating and exerting effector functions. However, little is known about how the binding of the ligands induce the PD1 inhibitory signal over T cells effector functions

Expansins have the remarkable ability to loosen plant cell walls and cellulose material without showing catalytic activity and therefore have potential applications in biomass degradation. To support the study of sequence‐structure‐function relationships and the search for novel expansins, the Expansin Engineering Database (ExED, https://exed.biocatnet.de) collected sequence and structure data on expansins

This article reports on the results of research aimed to translate biometric 3D face recognition concepts and algorithms into the field of protein biophysics in order to precisely and rapidly classify morphological features of protein surfaces. Both human faces and protein surfaces are free‐forms and some descriptors used in differential geometry can be used to describe them applying the principles

Dihydrolipoamide dehydrogenase (DLDH) is a mitochondrial enzyme that comprises an essential component of the pyruvate dehydrogenase complex. Lines of evidence have shown that many dehydrogenases possess unrelated actions known as moonlightings in addition to their oxidoreductase activity. As part of these activities, we have demonstrated that DLDH binds TiO2 as well as produces reactive oxygen species

Only about 0.3% of the entries in UniProt database have manually curated annotation. Annotation at the molecular level often relies on low‐throughput one‐protein‐at‐a‐time approach. Computational methods bridge this gap by assigning function based on sequence and/or fold similarity. Left‐handed beta helix (LbH) consists of three repeating six‐stranded beta‐strands forming an 18‐mer turn of the helix

The Rad50‐Mre11 nuclease complex plays a vital role in DNA repair in all domains of life. It recognizes and processes DNA double‐strand breaks. Rad50 proteins fold into an extended structure with a ~ 20‐60 nm long coiled coil connecting a globular ABC ATPase domain with a zinc hook dimerization domain. A published structure of an archaeal Rad50 zinc hook shows coiled coils pointing away from each other

S‐adenosyl‐L‐methionine (SAM)‐dependent methyltransferases (MTases) are widely distributed among almost all organisms and often characterized with conserved Rossmann fold, TIM barrel, and DxGxGxG motif. However, some MTases show no methyltransferase activity. In the present study, the crystal structure of LepI, one MTase‐like enzyme isolated from A. flavus that catalyzes pericyclic reactions, was investigated

High divergence in protein sequences makes the detection of distant protein relationships through homology‐based approaches challenging. Grouping protein sequences into families, through similarities in either sequence or 3‐D structure, facilitates in the improved recognition of protein relationships. In addition, strategically designed protein‐like sequences have been shown to bridge distant structural

Cytoplasmic activation/proliferation‐associated protein (Caprin) proteins assume diverse functions in many important biological processes, including synaptic plasticity, stress response, innate immune response, and cellular proliferation. The Caprin family members are characterized by the presence of a highly conserved homologous region (HR1) at the N‐terminus and arginine‐glycine‐rich (RGG) boxes

Natural products and natural product‐derived compounds have been widely used for pharmaceuticals for many years, and the search for new natural products that may have interesting activity is on going. Abyssomicins are natural product molecules that have antibiotic activity via inhibition of the folate synthesis pathway in microbiota. These compounds also appear to undergo a required [4+2] cycloaddition

It has been shown recently by Porter & Looger that a significant number of proteins exist that can form more than one stable fold. This note examines the sequences of these fold‐switching proteins by (a) calculating their foldability scores recently introduced by the present author and (b) comparing the propensity of chameleon sequences in fold switchers and in non fold switchers. It has been found

Isoflavonoid is one of the groups of flavonoids that play pivotal roles in the survival of land plants. Chalcone synthase (CHS), the first enzyme of the isoflavonoid biosynthetic pathway, catalyzes the formation of a common isoflavonoid precursor. We have previously reported that an isozyme of soybean CHS (termed GmCHS1) is a key component of the isoflavonoid metabolon, a protein complex to enhance

Allosteric communication is the basis of signaling and information transfer. Collective interactions between amino acid residues, which are spatially distributed in the three dimensional structure of a protein molecule, form the basis of allosteric network. While the construction of residue interaction graphs (RIG) is based on static crystal structures of proteins, it is important to extract information

Network theory methods and molecular dynamics (MD) simulations are accepted tools to study allosteric regulation. Indeed, dynamic networks built upon correlation analysis of MD trajectories provide detailed information about communication paths between distant sites. In this context, we aimed to understand whether the efficiency of intramolecular communication could be used to predict the allosteric

Protein Kinase‐Like Non‐Kinases (PKLNKs), commonly known as “pseudokinases”, are homologous to eukaryotic Ser/Thr/Tyr protein kinases (PKs) but lack the crucial aspartate residue in the catalytic loop, indispensable for phosphotransferase activity. Therefore, they are predicted to be “catalytically inactive” enzyme homologs. Analysis of protein‐kinase like sequences from Arabidopsis thaliana led to

Insulin has long been served as a model for protein aggregation, both due to the importance of aggregation in the manufacture of insulin and because the structural biology of insulin has been extensively characterized. Despite intensive study, details about the initial triggers for aggregation have remained elusive at the molecular level. We show here that at acidic pH, the aggregation of insulin is

The M42 aminopeptidases are a family of dinuclear aminopeptidases widely distributed in Prokaryotes. They are potentially associated to the proteasome, achieving complete peptide destruction. Their most peculiar characteristic is their quaternary structure, a tetrahedron‐shaped particle made of twelve subunits. The catalytic site of M42 aminopeptidases is defined by seven conserved residues. Five of

We have modeled modifications of a known ligand to the SARS‐CoV‐2 (COVID‐19) protease, that can form a covalent adduct, plus additional ligand‐protein hydrogen bonds.

Crystal structures of diverse protein kinase catalytic subunits reveal a number of water molecules whose positions within the protein core are better preserved than amino acid types in many functionally important locations. It remains unknown whether they play any particular role, and whether their removal, disturbing local interaction patterns to no smaller degree than amino acid mutations, can affect

Recent work has revealed that the association of a disordered region of a protein with a folded binding partner can occur as rapidly as association between two folded proteins. This is the case for the phosphatase calcineurin (CaN) and its association with its activator calmodulin. Calmodulin binds to the intrinsically disordered regulatory domain of CaN. Previous studies have shown that electrostatic

The focal adhesion kinase (FAK) and the proline‐rich tyrosine kinase 2‐beta (PYK2) are implicated in cancer progression and metastasis and represent promising biomarkers and targets for cancer therapy. FAK and PYK2 are recruited to Focal Adhesions (FAs) via interactions between their Focal Adhesion Targeting (FAT) domains and conserved segments (LD motifs) on the proteins Paxillin, Leupaxin and Hic‐5

Intrinsically disordered regions (IDR) play an important role in key biological processes and are closely related to human diseases. IDRs have great potential to serve as targets for drug discovery, most notably in disordered binding regions. Accurate prediction of IDRs is challenging because their genome wide occurrence and a low ratio of disordered residues make them difficult targets for traditional

Alzheimer's disease is one of the most common causes of dementia. It is believed that the aggregation of short Aβ ‐peptides to form oligomeric and protofibrillar amyloid assemblies plays a central role for disease‐relevant neurotoxicity. In recent years, passive immunotherapy has been introduced as a potential treatment strategy with anti‐amyloid antibodies binding to Aβ ‐amyloids and inducing their

Protein‐protein interactions (PPIs) are ubiquitous and functionally of great importance in biological systems. Hence, the accurate prediction of PPIs by protein‐protein docking and scoring tools is highly desirable in order to characterize their structure and biological function. Ab initio docking protocols are divided into the sampling of docking poses to produce at least one near‐native structure

CAPRI challenges offer a variety of blind tests for protein‐protein interaction prediction. In CAPRI Rounds 38‐45, we generated a set of putative binding modes for each target with an FFT‐based docking algorithm, and then scored and ranked these binding modes with a proprietary scoring function, ITScorePP. We have also developed a novel web server, Rebipp. The algorithm utilizes information retrieval

Protein docking algorithms aim to predict the 3D structure of a protein complex from the structures of its separated components. In the past, most docking algorithms focused on docking pairs of proteins to form dimeric complexes. However, attention is now turning towards the more difficult problem of using docking methods to predict the structures of multicomponent complexes. In both cases, however

Supply of iron into human cells is achieved by iron carrier protein transferrin and its receptor that upon complex formation get internalized by endocytosis. Similarly, the iron needs to be delivered into the brain, and necessitates the transport across the blood‐brain barrier. While there are still unanswered questions about these mechanisms, extensive efforts have been made to use the system for

Proteins are the active players in performing essential molecular activities throughout biology, and their dynamics has been broadly demonstrated to relate to their mechanisms. The intrinsic fluctuations have often been used to represent their dynamics and then compared to the experimental B‐factors. However, proteins do not move in a vacuum and their motions are modulated by solvent that can impose

Amyloid‐beta (Aβ) protein is related to Alzheimer disease (AD), and various experiments have shown that oligomers as small as dimers are cytotoxic. Recent studies have concluded that interactions of Aβ with neuronal cell membranes lead to disruption of membrane integrity and toxicity and they play a key role in the development of AD. Molecular dynamics (MD) simulations have been used to investigate

The ryanodine receptors (RyR) are essential to calcium signaling in striated muscles. A deep understanding of the complex Ca2+‐activation/inhibition mechanism of RyRs requires detailed structural and dynamic information for RyRs in different functional states (eg, with Ca2+ bound to activating or inhibitory sites). Recently, high‐resolution structures of the RyR isoform 1 (RyR1) were solved by cryo‐electron

Protein domains exist by themselves or in combination with other domains to form complex multidomain proteins. Defining domain boundaries in proteins is essential for understanding their evolution and function but is not trivial. More specifically, partitioning domains that interact by forming a single β‐sheet is known to be particularly troublesome for automatic structure‐based domain decomposition

Mutual information and entropy transfer analysis employed on two inactive states of human beta‐2 adrenergic receptor (β2‐AR) unraveled distinct communication pathways. Previously, a so‐called “highly” inactive state of the receptor was observed during 1.5 microsecond long molecular dynamics simulation where the largest intracellular loop (ICL3) was swiftly packed onto the G‐protein binding cavity,

Pentapeptide repeat proteins (PRPs) represent a large superfamily with more than 38 000 sequences in nearly 3500 species, the majority belonging to cyanobacteria but represented among all branches of life. PRPs contain at least eight consecutive pentapeptide repeats with the consensus (A/C/S/V/T/L/I)(D/N/S/K/E/I/R)(L/F)(S/T/R/E/Q/K/V/D)(G/D/E/N/R/Q/K). PRPs fold into right‐handed quadrilateral β helices

Coronavirus disease 2019 (COVID‐19) is a pandemic infectious disease caused by novel severe acute respiratory syndrome coronavirus‐2 (SARS CoV‐2). The SARS CoV‐2 is transmitted more rapidly and readily than SARS CoV. Both, SARS CoV and SARS CoV‐2 via their glycosylated spike proteins recognize the human angiotensin converting enzyme‐2 (ACE‐2) receptor. We generated multiple sequence alignments and

Structural characterization of alternatively folded and partially disordered protein conformations remains challenging. Outer surface protein A (OspA) is a pivotal protein in Borrelia infection, which is the etiological agent of Lyme disease. OspA exists in equilibrium with intermediate conformations, in which the central and the C‐terminal regions of the protein have lower stabilities than the N‐terminal

Mixed lineage leukemia protein (MLL1 protein) recognizes the CpG site via its CXXC domain and is frequently associated with leukemia. The specific recognition is abolished by C1188D mutation, which also prevents MLL‐related leukemia. In this paper, multiple molecular dynamic (MD) simulations were performed to investigate the mechanism of recognition and influences of C1188D mutation. Started from fully

Understanding the determinants of antibody specificity is one of the challenging tasks in antibody development. Monospecific antibodies are still dominant in approved antibody therapeutics but there is a significant body of work to show that multispecific antibodies can increase the overall therapeutic effect. Dual‐specific or “Two‐in‐One” antibodies can bind to two different antigens separately with

Tyrosine phosphorylation, a highly regulated post‐translational modification, is carried out by the enzyme tyrosine kinase (TK). TKs are important mediators in signaling cascades, facilitating diverse biological processes in response to stimuli. TKs may acquire mutations leading to malignancy and are viable targets for anti‐cancer drugs. Mast/stem cell growth factor receptor KIT is a TK involved in

Sortases are a group of enzymes displayed on the cell‐wall of Gram‐positive bacteria. They are responsible for the attachment of virulence factors onto the peptidoglycan in a transpeptidation reaction through recognition of a pentapeptide substrate. Most housekeeping sortases recognize one specific pentapeptide motif; however, Streptococcus pyogenes sortase A (SpSrtA WT) recognizes LPETG, LPETA and