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Computational and Mathematical Methods... 2014By introducing the descriptors calculated from the molecular structure, the binding rates of plasma protein (BRPP) with seventy diverse drugs are modeled by a... (Comparative Study)
Comparative Study
By introducing the descriptors calculated from the molecular structure, the binding rates of plasma protein (BRPP) with seventy diverse drugs are modeled by a quantitative structure-activity relationship (QSAR) technique. Two algorithms, heuristic algorithm (HA) and support vector machine (SVM), are used to establish linear and nonlinear models to forecast BRPP. Empirical analysis shows that there are good performances for HA and SVM with cross-validation correlation coefficients Rcv(2) of 0.80 and 0.83. Comparing HA with SVM, it was found that SVM has more stability and more robustness to forecast BRPP.
Topics: Blood Proteins; Humans; Linear Models; Models, Theoretical; Pharmaceutical Preparations; Protein Binding; Quantitative Structure-Activity Relationship; Support Vector Machine
PubMed: 25161695
DOI: 10.1155/2014/957154 -
Journal of Computational Chemistry Feb 2005A Monte Carlo method is given to compute the binding affinity of a ligand to a protein. The method involves extending configuration space by a discrete variable...
A Monte Carlo method is given to compute the binding affinity of a ligand to a protein. The method involves extending configuration space by a discrete variable indicating whether the ligand is bound to the protein and a special Monte Carlo move, which allows transitions between the unbound and bound states. Provided that an accurate protein structure is given, that the protein-ligand binding site is known, and that an accurate chemical force field together with a continuum solvation model is used, this method provides a quantitative estimate of the free energy of binding.
Topics: Binding Sites; Computer Simulation; Ligands; Models, Chemical; Monte Carlo Method; Protein Binding; Thermodynamics
PubMed: 15614799
DOI: 10.1002/jcc.20167 -
The AAPS Journal Mar 2016
Comparative Study Review
Topics: Chemistry, Pharmaceutical; Humans; Ligands; Pharmaceutical Preparations; Protein Binding
PubMed: 26669789
DOI: 10.1208/s12248-015-9855-0 -
Plant & Cell Physiology Jun 2017Late embryogenesis abundant (LEA) proteins are widely distributed among plant species, where they contribute to abiotic stress tolerance. LEA proteins can be classified...
Late embryogenesis abundant (LEA) proteins are widely distributed among plant species, where they contribute to abiotic stress tolerance. LEA proteins can be classified into seven groups according to conserved sequence motifs. The PM1 protein from soybean, which belongs to the Pfam LEA_1 group, has been shown previously to be at least partially natively unfolded, to bind metal ions and potentially to stabilize proteins and membranes. Here, we investigated the role of the PM1 C-terminal domain and in particular the multiple histidine residues in this half of the protein. We constructed recombinant plasmids expressing full-length PM1 and two truncated forms, PM1-N and PM1-C, which represent the N- and C-terminal halves of the protein, respectively. Immunoblotting and cross-linking experiments showed that full-length PM1 forms oligomers and high molecular weight (HMW) complexes in vitro and in vivo, while PM1-C, but not PM1-N, also formed oligomers and HMW complexes in vitro. When the histidine residues in PM1 and PM1-C were chemically modified, oligomerization was abolished, suggesting that histidines play a key role in this process. Furthermore, we demonstrated that high Cu2+ concentrations promote oligomerization and induce PM1 and PM1-C to form HMW complexes. Therefore, we speculate that PM1 proteins not only maintain ion homeostasis in the cytoplasm, but also potentially stabilize and protect other proteins during abiotic stress by forming a large, oligomeric molecular shield around biological targets.
Topics: Copper; Histidine; Plant Proteins; Protein Binding; Protein Multimerization; Protein Structure, Secondary; Glycine max
PubMed: 28387856
DOI: 10.1093/pcp/pcx046 -
Histology and Histopathology Aug 2014Cellular migration is a fundamental biological process occurring as early as embryogenesis to the pathological state of cancer metastasis. Nearly all cellular migrations... (Review)
Review
Cellular migration is a fundamental biological process occurring as early as embryogenesis to the pathological state of cancer metastasis. Nearly all cellular migrations involve an extracellular signal that is transduced internally by members of a signalling cascade. These signal transduction events are driven by protein-protein interactions (PPIs) that coordinate intracellular activities to enable a cell to migrate. Understanding these PPIs will provide valuable insight into how cellular migration can be modulated perhaps towards a therapeutic end. Histologically, not many techniques are available to demonstrate PPIs. Contrasting agents only demonstrate the presence of a particular protein, and perhaps its co-localisation with another protein. Yet, co-localisation need not necessarily indicate physical interaction between the two proteins. In this review, we highlight four commonly used methods that continue to expand our understanding of PPIs underlying cell migration: co-immunoprecipitation, bimolecular fluorescence complementation, proximity ligation assay and surface plasmon resonance. The methods discussed herein allow for the study of PPIs in a wide variety of biological samples, including cell lysates, live cells, fixed cells and tissues, enabling the quantification of endogenous PPIs and exploration of the nature of PPIs. We also include a rudimentary framework for researchers to decide which experimental method best suits their research goals.
Topics: Animals; Cell Movement; Humans; Immunoprecipitation; Protein Binding; Proteins
PubMed: 24549517
DOI: 10.14670/HH-29.965 -
Pharmaceutical Research Jul 2003The aim of this study was to reduce or prevent nonspecific binding (NSB) of compounds to ultrafiltration (UF) protein binding (PB) testing units.
PURPOSE
The aim of this study was to reduce or prevent nonspecific binding (NSB) of compounds to ultrafiltration (UF) protein binding (PB) testing units.
METHODS
UF units (regenerated cellulose, MWCO 10K) were used for PB and NSB measurements with or without pretreatment with 5% tween 80 (TW 80) or 5% benzalkonium chloride (BAK) on the filter membrane. Dosing solutions (10 microM) in human serum and pH 7.4 phosphate-buffered saline were centrifuged at 3,000 g and room temperature after 1-h incubation in UF testing units. In parallel, a 96-well equilibrium dialyzer was used for PB and NSB measurements in equilibrium dialysis (ED) at 37 degrees C for 4 h. Samples of UF and ED were analyzed by LC/MS or LSC.
RESULTS
Severe NSB was observed for etoposide, hydrocortisone, propranolol, and vinblastine in UF. In contrast, TW 80 or BAK pre-treatment on the filter membrane decreased the NSB from 87-95% to 13-64% without causing a significant change in membrane integrity. When NSB was below 50% as a result of pretreating agents, PB data of marker compounds were comparable to those of ED.
CONCLUSIONS
The pretreated membrane with TW 80 or BAK showed significantly less NSB for compounds that had a tendency toward high membrane binding. A modified UF method with pretreatment improved the performance of UF and was able to produce comparable PB results to ED.
Topics: Blood Proteins; Humans; Pharmaceutical Preparations; Protein Binding; Ultrafiltration
PubMed: 12880287
DOI: 10.1023/a:1024406221962 -
Chembiochem : a European Journal of... May 2019Protein-protein interactions (PPIs) are an effective means to orchestrate intricate biological processes required to sustain life. Approximately 650 000 PPIs underlie... (Review)
Review
Protein-protein interactions (PPIs) are an effective means to orchestrate intricate biological processes required to sustain life. Approximately 650 000 PPIs underlie the human interactome; thus underscoring its complexity and the manifold signaling outputs altered in response to changes in specific PPIs. This minireview illustrates the growing arsenal of PPI assemblies and offers insights into how these varied PPI regulatory modalities are relevant to customized drug discovery, with a focus on cancer. First, known and emerging PPIs and PPI-targeted drugs of both natural and synthetic origin are categorized. Building on these discussions, the merits of PPI-guided therapeutics over traditional drug design are discussed. Finally, a compare-and-contrast section for different PPI blockers, with gain-of-function PPI interventions, such as PROTACS, is provided.
Topics: Animals; Drug Discovery; Humans; Protein Binding; Protein Multimerization; Proteins
PubMed: 30589188
DOI: 10.1002/cbic.201800716 -
Proceedings of the National Academy of... Aug 2008Allostery, the coupling between ligand binding and protein conformational change, is the heart of biological network and it has often been explained by two...
Allostery, the coupling between ligand binding and protein conformational change, is the heart of biological network and it has often been explained by two representative models, the induced-fit and the population-shift models. Here, we clarified for what systems one model fits better than the other by performing molecular simulations of coupled binding and conformational change. Based on the dynamic energy landscape view, we developed an implicit ligand-binding model combined with the double-basin Hamiltonian that describes conformational change. From model simulations performed for a broad range of parameters, we uncovered that each of the two models has its own range of applicability, stronger and longer-ranged interaction between ligand and protein favors the induced-fit model, and weaker and shorter-ranged interaction leads to the population-shift model. We further postulate that the protein binding to small ligand tends to proceed via the population-shift model, whereas the protein docking to macromolecules such as DNA tends to fit the induced-fit model.
Topics: Antibodies, Monoclonal; DNA; Ligands; Models, Molecular; Protein Binding; Protein Structure, Quaternary
PubMed: 18678900
DOI: 10.1073/pnas.0802524105 -
Angewandte Chemie (International Ed. in... Apr 2019Sac7d is a small, thermostable protein that induces large helical deformations in DNA upon association. Starting from multiple initial placements of the unbound Sac7d...
Sac7d is a small, thermostable protein that induces large helical deformations in DNA upon association. Starting from multiple initial placements of the unbound Sac7d structure relative to a B-DNA oligonucleotide, molecular dynamics (MD) simulations were employed to directly follow several successful binding events at atomic resolution that resulted in structures in close agreement with the native complex geometry. The final native complex formed rapidly within tenths of nanoseconds and included simultaneous large-scale kinking, groove opening, twisting, and intercalation in the target DNA. The simulations indicate that the complex formation process involves initial non-native contacts that helped in reaching the final bound state, with residues intercalated at the center of the kinked DNA. It was also possible to identify several long-lived trapped intermediate states of the binding process and to follow sliding processes of Sac7d along the DNA minor groove.
Topics: DNA; Molecular Dynamics Simulation; Molecular Structure; Protein Binding
PubMed: 30767392
DOI: 10.1002/anie.201900935 -
Structure (London, England : 1993) Dec 2004Protein-protein association is often accompanied by changes in receptor and ligand structure. This interplay between protein flexibility and protein-protein recognition...
Protein-protein association is often accompanied by changes in receptor and ligand structure. This interplay between protein flexibility and protein-protein recognition is currently the largest obstacle both to our understanding of and to the reliable prediction of protein complexes. We performed two sets of molecular dynamics simulations for the unbound receptor and ligand structures of 17 protein complexes and applied shape-driven rigid body docking to all combinations of representative snapshots. The crossdocking of structure ensembles increased the likelihood of finding near-native solutions. The free ensembles appeared to contain multiple complementary conformations. These were in general not related to the bound structure. We suggest that protein-protein binding follows a three-step mechanism of diffusion, free conformer selection, and refolding. This model combines previously conflicting ideas and is in better agreement with the current data on interaction forces, time scales, and kinetics.
Topics: Models, Molecular; Protein Binding; Protein Structure, Tertiary; Proteins
PubMed: 15576027
DOI: 10.1016/j.str.2004.09.014