Several properties of amino acid sequences corresponding to proteins that are known to fold are compared to those of randomly generated sequences and to sequences of intrinsically disordered proteins ...in order to find properties that distinguish folding sequences from the rest. The properties studied included helix and sheet propensities from secondary structure prediction, adjacency correlations, directionality correlations, as well as propensities of all possible triplets and quadruplets. Small differences between known folded and random sequences were observed for the adjacency and directional correlations, and significant differences were seen on the triplet and especially on the quadruplet propensities. Based on the differences in the adjacency, triplet or quadruplet propensities folding scores were defined and used to test the accuracy of foldability prediction based on these statistics. The best predictions were obtained from the quadruplet propensities.
The various biases affecting RNA mutations during evolution is the subject of intense research, leaving the extent of the role of random mutations undefined. To remedy this lacuna, using the codon ...table, the number of codons representing each amino acid was correlated with the amino acid frequencies in different branches of the evolutionary tree. The correlations were seen to increase as evolution progressed. Furthermore, the number of RNA mutations that resulted in a given amino acid mutation were found to be correlated with several widely used amino acid similarity tables (used in sequence alignments). These correlations were seen to increase when the observed codon usage was factored in.
Recent work showed that there is a significant difference between the statistics of amino acid triplets and quadruplets in sequences of folded proteins and randomly generated sequences. These ...statistics were used to assign a score to each sequence and make a prediction whether a sequence is likely to fold. The present paper extends the statistics to higher multiplets and suggests a way to handle the treatment of multiplets that were not found in the set of folded proteins. In particular, foldability predictions were done along the line of the previous work using pentuplet statistics and a way was found to combine the quadruplet and pentuplets statistics to improve the foldability predictions. A different, simpler, score was defined for hextuplets and heptuplets and were used to predict the direction of stability change of a protein upon mutation. With the best score combination the accuracy of the prediction was 73.4%.
The steady growth of the Protein Data Bank (PDB) suggests the periodic repetition of searches for sequences that form different secondary structures in different protein structures; these are called ...chameleon sequences. This paper presents a fast (nlog(n)) algorithm for such searches and presents the results on all protein structures in the PDB. The longest such sequence found consists of 20 residues.
Molecular docking has become an increasingly important tool for drug discovery. In this review, we present a brief introduction of the available molecular docking methods, and their development and ...applications in drug discovery. The relevant basic theories, including sampling algorithms and scoring functions, are summarized. The differences in and performance of available docking software are also discussed. Flexible receptor molecular docking approaches, especially those including backbone flexibility in receptors, are a challenge for available docking methods. A recently developed Local Move Monte Carlo (LMMC) based approach is introduced as a potential solution to flexible receptor docking problems. Three application examples of molecular docking approaches for drug discovery are provided.
(GPCR)The receptor for TSH receptor (TSHR), a G protein coupled receptor (GPCR), is of particular interest as the primary antigen in autoimmune hyperthyroidism (Graves' disease) caused by stimulating ...TSHR antibodies. To date, only one domain of the extracellular region of the TSHR has been crystallized. We have run a 1000 ns molecular dynamic simulation on a model of the entire TSHR generated by merging the extracellular region of the receptor, obtained using artificial intelligence, with our recent homology model of the transmembrane domain, embedded it in a lipid membrane and solvated it with water and counterions. The simulations showed that the structure of the transmembrane and leucine-rich domains were remarkably constant while the linker region (LR), known more commonly as the 'hinge region,' showed significant flexibility, forming several transient secondary structural elements. Furthermore, the relative orientation of the leucine-rich domain with the rest of the receptor was also seen to be variable. These data suggest that this LR is an intrinsically disordered protein. Furthermore, preliminary data simulating the full TSHR model complexed with its ligand (TSH) showed that (a) there is a strong affinity between the LR and TSH ligand and (b) the association of the LR and the TSH ligand reduces the structural fluctuations in the LR. This full-length model illustrates the importance of the LR in responding to ligand binding and lays the foundation for studies of pathologic TSHR autoantibodies complexed with the TSHR to give further insight into their interaction with the flexible LR.
The properties of 1172 protein complexes (downloaded from the Protein Data Bank (PDB)) have been studied based on the concept of circular variance as a buriedness indicator and the concept of mutual ...proximity as a parameter-free definition of contact. The propensities of residues to be in the protein, on the surface or form contact, as well as residue pairs to form contact were calculated. In addition, the concept of circular variance has been used to compare the ruggedness and shape of the contact surface with the overall surface.
An algorithm is presented for the simulation of two partially flexible macromolecules where the interaction between the flexible parts and rigid parts is represented by energy grids associated with ...the rigid part of each macromolecule. The proposed algorithm avoids the transformation of the grid upon molecular movement at the expense of the significantly lesser effect of transforming the flexible part.
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 that the average foldability score of the fold switchers indicates weaker foldability. As for the propensity of chameleon sequences of length 5 to 7 it was found, somewhat surprisingly, that there is only a very small difference between the fold switchers and the non fold switchers. Furthermore, when looking at amino acid propensities, for several amino acids there was even an opposing trend in the deviation of their propensities from the overall amino acid propensities.
TSH receptor (TSHR) antibodies are the cause of Graves’ disease and may also be found in patients with Hashimoto’s thyroiditis. They come in at least three varieties: thyroid stimulating, thyroid ...blocking and neutral. The measurement of TSH receptor antibodies in Graves’ disease and Hashimoto’s thyroiditis is a common clinical activity and can be useful in diagnosis and prognosis. We show that it is not possible to detect the blocking variety of TSHR antibody in patients with Graves’ disease because the stimulating antibody may overwhelm the measurement of blocking in the bioassays available for their measurement and may blind the valid interpretation of the results. To help explain this in more detail we show a series of studies with monoclonal TSHR antibodies which support this conclusion.
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