Flexible protein alignment and hinge detection

2002 ◽  
Vol 48 (2) ◽  
pp. 242-256 ◽  
Author(s):  
Maxim Shatsky ◽  
Ruth Nussinov ◽  
Haim J. Wolfson
Keyword(s):  
Protein Alignment ◽  
Flexible Protein

Modelling Flexible Protein-Ligand Binding in p38α MAP Kinase using the QUBE Force Field

2019 ◽  
Author(s):  
Joshua Horton ◽  
Alice Allen ◽  
Daniel Cole
Keyword(s):  
Quantum Mechanics ◽  
Force Field ◽  
Map Kinase ◽  
Binding Free Energy ◽  
Quantum Mechanical ◽  
Enhanced Sampling ◽  
Relative Binding ◽  
Stringent Test ◽  
Flexible Protein ◽  
P38α Map Kinase

<div><div><div><p>The quantum mechanical bespoke (QUBE) force field is used to retrospectively calculate the relative binding free energy of a series of 17 flexible inhibitors of p38α MAP kinase. The size and flexibility of the chosen molecules represent a stringent test of the derivation of force field parameters from quantum mechanics, and enhanced sampling is required to reduce the dependence of the results on the starting structure. Competitive accuracy with a widely-used biological force field is achieved, indicating that quantum mechanics derived force fields are approaching the accuracy required to provide guidance in prospective drug discovery campaigns.</p></div></div></div>

scholarly journals Alterations in ZnT1 expression and function lead to impaired intracellular zinc homeostasis in cancer

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Adrian Israel Lehvy ◽  
Guy Horev ◽  
Yarden Golan ◽  
Fabian Glaser ◽  
Yael Shammai ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Zinc Homeostasis ◽  
Healthy Population ◽  
Missense Mutations ◽  
Protein Alignment ◽  
Loss Of Function ◽  
Intracellular Zinc ◽  
Dismal Prognosis ◽  
Zinc Levels ◽  
And Function

Abstract Zinc is vital for the structure and function of ~3000 human proteins and hence plays key physiological roles. Consequently, impaired zinc homeostasis is associated with various human diseases including cancer. Intracellular zinc levels are tightly regulated by two families of zinc transporters: ZIPs and ZnTs; ZIPs import zinc into the cytosol from the extracellular milieu, or from the lumen of organelles into the cytoplasm. In contrast, the vast majority of ZnTs compartmentalize zinc within organelles, whereas the ubiquitously expressed ZnT1 is the sole zinc exporter. Herein, we explored the hypothesis that qualitative and quantitative alterations in ZnT1 activity impair cellular zinc homeostasis in cancer. Towards this end, we first used bioinformatics to analyze inactivating mutations in ZIPs and ZNTs, catalogued in the COSMIC and gnomAD databases, representing tumor specimens and healthy population controls, respectively. ZnT1, ZnT10, ZIP8, and ZIP10 showed extremely high rates of loss of function mutations in cancer as compared to healthy controls. Analysis of the putative functional impact of missense mutations in ZnT1-ZnT10 and ZIP1-ZIP14, using homologous protein alignment and structural predictions, revealed that ZnT1 displays a markedly increased frequency of predicted functionally deleterious mutations in malignant tumors, as compared to a healthy population. Furthermore, examination of ZnT1 expression in 30 cancer types in the TCGA database revealed five tumor types with significant ZnT1 overexpression, which predicted dismal prognosis for cancer patient survival. Novel functional zinc transport assays, which allowed for the indirect measurement of cytosolic zinc levels, established that wild type ZnT1 overexpression results in low intracellular zinc levels. In contrast, overexpression of predicted deleterious ZnT1 missense mutations did not reduce intracellular zinc levels, validating eight missense mutations as loss of function (LoF) mutations. Thus, alterations in ZnT1 expression and LoF mutations in ZnT1 provide a molecular mechanism for impaired zinc homeostasis in cancer formation and/or progression.

Conformational Properties of the Chemotherapeutic Drug Analogue Epothilone A: How to Model a Flexible Protein Ligand Using Scarcely Available Experimental Data

2019 ◽  
Vol 59 (5) ◽  
pp. 2218-2230 ◽  
Author(s):  
Jožica Dolenc ◽  
Wilfred F. van Gunsteren ◽  
Andrea E. Prota ◽  
Michel O. Steinmetz ◽  
John H. Missimer
Keyword(s):  
Experimental Data ◽  
Chemotherapeutic Drug ◽  
Epothilone A ◽  
Conformational Properties ◽  
Flexible Protein

scholarly journals Efficient protein alignment algorithm for protein search

2010 ◽  
Vol 11 (Suppl 1) ◽  
pp. S34 ◽  
Author(s):  
Zaixin Lu ◽  
Zhiyu Zhao ◽  
Bin Fu
Keyword(s):  
Alignment Algorithm ◽  
Protein Alignment

scholarly journals Efficient alternatives to PSI-BLAST

2012 ◽  
Vol 60 (3) ◽  
pp. 495-505
Author(s):  
M. Startek ◽  
S. Lasota ◽  
M. Sykulski ◽  
A. Bułak ◽  
L. Noé ◽  
...  
Keyword(s):  
Amino Acid ◽  
Finite Automata ◽  
Protein Family ◽  
Homology Search ◽  
Amino Acid Residues ◽  
Protein Alignment ◽  
Substitution Model ◽  
Hierarchical Tree ◽  
Context Specific ◽  
Ncbi Blast

Abstract In this paper we present two algorithms that may serve as efficient alternatives to the well-known PSI BLAST tool: SeedBLAST and CTX-PSI Blast. Both may benefit from the knowledge about amino acid composition specific to a given protein family: SeedBLAST uses the advisedly designed seed, while CTX-PSI BLAST extends PSI BLAST with the context-specific substitution model. The seeding technique became central in the theory of sequence alignment. There are several efficient tools applying seeds to DNA homology search, but not to protein homology search. In this paper we fill this gap. We advocate the use of multiple subset seeds derived from a hierarchical tree of amino acid residues. Our method computes, by an evolutionary algorithm, seeds that are specifically designed for a given protein family. The seeds are represented by deterministic finite automata (DFAs) and built into the NCBI-BLAST software. This extended tool, named SeedBLAST, is compared to the original BLAST and PSI-BLAST on several protein families. Our results demonstrate a superiority of SeedBLAST in terms of efficiency, especially in the case of twilight zone hits. The contextual substitution model has been proven to increase sensitivity of protein alignment. In this paper we perform a next step in the contextual alignment program. We announce a contextual version of the PSI-BLAST algorithm, an iterative version of the NCBI-BLAST tool. The experimental evaluation has been performed demonstrating a significantly higher sensitivity compared to the ordinary PSI-BLAST algorithm.

scholarly journals Energy-Filtered Electron Microscopy Reveals that Talin is a Highly Flexible Protein Composed of a Series of Globular Domains

1997 ◽  
Vol 243 (1-2) ◽  
pp. 430-436 ◽  
Author(s):  
Jorg Winkler ◽  
Heinrich Lunsdorf ◽  
Brigitte M. Jockusch
Keyword(s):  
Electron Microscopy ◽  
Flexible Protein

scholarly journals All-Atom MD Simulations of the HBV Capsid Complexed with AT130 Reveal Secondary and Tertiary Structural Changes and Mechanisms of Allostery

2021 ◽  
Author(s):  
Carolina Pérez Segura ◽  
Boon Chong Goh ◽  
Jodi A. Hadden-Perilla
Keyword(s):  
Small Molecules ◽  
Drug Target ◽  
Structural Changes ◽  
Salt Bridge ◽  
Md Simulations ◽  
Health Concern ◽  
Protein Dimer ◽  
B Virus ◽  
Flexible Protein ◽  
Dynamics Simulations

AbstractThe hepatitis B virus (HBV) capsid is an attractive drug target, relevant to combating viral hepatitis as a major public health concern. Among small molecules known to interfere with capsid assembly, the phenylpropenamides, including AT130, represent an important anti-viral paradigm based on disrupting the timing of genome encapsulation. Crystallographic studies of AT130-bound complexes have been essential in explaining the effects of the small molecule on HBV capsid structure; however, computational examination reveals that key changes attributed to AT130 were erroneous, likely a consequence of interpreting poor resolution arising from a highly flexible protein. Here, all-atom molecular dynamics simulations of an intact AT130-bound HBV capsid reveal that, rather than damaging spike helicity, AT130 enhances the capsid’s ability to recover it. A new conformational state is identified, which can lead to dramatic opening of the intradimer interface and disruption of communication within the spike tip. A novel salt bridge is also discovered, which can mediate contact between the spike tip and fulcrum even in closed conformations, revealing a mechanism of direct communication across these domains. Combined with dynamical network analysis, results describe a connection between the intra- and interdimer interfaces and enable mapping of allostery traversing the entire capsid protein dimer.

scholarly journals A Sequential Segment Based Alpha-Helical Transmembrane Protein Alignment Method

2018 ◽  
Vol 14 (8) ◽  
pp. 901-906 ◽  
Author(s):  
Han Wang ◽  
Jingru Wang ◽  
Li Zhang ◽  
Pingping Sun ◽  
Ning Du ◽  
...  
Keyword(s):  
Transmembrane Protein ◽  
Alignment Method ◽  
Protein Alignment
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