Computational Refinement of Functional Single Nucleotide Polymorphisms Associated with ATM Gene

gene are the most common forms of genetic variations that account for various forms of cancer. However, the extent to which SNPs interferes with the gene regulation and affects cancer susceptibility remains largely unknown. gene. gene function can aid in better understanding of genetic differences in disease susceptibility

UBI-XGB: IDENTIFICATION OF UBIQUITIN PROTEINS USING MACHINE LEARNING MODEL

A recent line of research has focused on Ubiquitination, a pervasive and proteasome-mediated protein degradation that controls apoptosis and is crucial in the breakdown of proteins and the development of cell disorders, is a major factor.  The turnover of proteins and ubiquitination are two related processes. We predict ubiquitination sites; these attributes are lastly fed into the extreme gradient boosting (XGBoost) classifier. We develop reliable predictors computational tool using experimental identification of protein ubiquitination sites is typically labor- and time-intensive. First, we encoded protein sequence features into matrix data using Dipeptide Deviation from Expected Mean (DDE) features encoding techniques. We also proposed 2nd features extraction model named dipeptide composition (DPC) model. It is vital to develop reliable predictors since experimental identification of protein ubiquitination sites is typically labor- and time-intensive. In this paper, we proposed computational method as named Ubipro-XGBoost, a multi-view feature-based technique for predicting ubiquitination sites. Recent developments in proteomic technology have sparked renewed interest in the identification of ubiquitination sites in a number of human disorders, which have been studied experimentally and clinically.  When more experimentally verified ubiquitination sites appear, we developed a predictive algorithm that can locate lysine ubiquitination sites in large-scale proteome data. This paper introduces Ubipro-XGBoost, a machine learning method. Ubipro-XGBoost had an AUC (area under the Receiver Operating Characteristic curve) of 0.914% accuracy, 0.836% Sensitivity, 0.992% Specificity, and 0.839% MCC on a 5-fold cross validation based on DPC model, and 2nd 0.909% accuracy, 0.839% Sensitivity, 0.979% Specificity, and 0. 0.829% MCC on a 5-fold cross validation based on DDE model. The findings demonstrate that the suggested technique, Ubipro-XGBoost, outperforms conventional ubiquitination prediction methods and offers fresh advice for ubiquitination site identification

Patterns and Signals of Biology: An Emphasis On The Role of Post Translational Modifications in Proteomes for Function and Evolutionary Progression

After synthesis, a protein is still immature until it has been customized for a specific task. Post-translational modifications (PTMs) are steps in biosynthesis to perform this customization of protein for unique functionalities. PTMs are also important to protein survival because they rapidly enable protein adaptation to environmental stress factors by conformation change. The overarching contribution of this thesis is the construction of a computational profiling framework for the study of biological signals stemming from PTMs associated with stressed proteins. In particular, this work has been developed to predict and detect the biological mechanisms involved in types of stress response with PTMs in mitochondrial (Mt) and non-Mt protein. Before any mechanism can be studied, there must first be some evidence of its existence. This evidence takes the form of signals such as biases of biological actors and types of protein interaction. Our framework has been developed to locate these signals, distilled from “Big Data” resources such as public databases and the the entire PubMed literature corpus. We apply this framework to study the signals to learn about protein stress responses involving PTMs, modification sites (MSs). We developed of this framework, and its approach to analysis, according to three main facets: (1) by statistical evaluation to determine patterns of signal dominance throughout large volumes of data, (2) by signal location to track down the regions where the mechanisms must be found according to the types and numbers of associated actors at relevant regions in protein, and (3) by text mining to determine how these signals have been previously investigated by researchers. The results gained from our framework enable us to uncover the PTM actors, MSs and protein domains which are the major components of particular stress response mechanisms and may play roles in protein malfunction and disease

Detection and characterization of 3D-signature phosphorylation site motifs and their contribution towards improved phosphorylation site prediction in proteins

<p>Abstract</p> <p>Background</p> <p>Phosphorylation of proteins plays a crucial role in the regulation and activation of metabolic and signaling pathways and constitutes an important target for pharmaceutical intervention. Central to the phosphorylation process is the recognition of specific target sites by protein kinases followed by the covalent attachment of phosphate groups to the amino acids serine, threonine, or tyrosine. The experimental identification as well as computational prediction of phosphorylation sites (P-sites) has proved to be a challenging problem. Computational methods have focused primarily on extracting predictive features from the local, one-dimensional sequence information surrounding phosphorylation sites.</p> <p>Results</p> <p>We characterized the spatial context of phosphorylation sites and assessed its usability for improved phosphorylation site predictions. We identified 750 non-redundant, experimentally verified sites with three-dimensional (3D) structural information available in the protein data bank (PDB) and grouped them according to their respective kinase family. We studied the spatial distribution of amino acids around phosphorserines, phosphothreonines, and phosphotyrosines to extract signature 3D-profiles. Characteristic spatial distributions of amino acid residue types around phosphorylation sites were indeed discernable, especially when kinase-family-specific target sites were analyzed. To test the added value of using spatial information for the computational prediction of phosphorylation sites, Support Vector Machines were applied using both sequence as well as structural information. When compared to sequence-only based prediction methods, a small but consistent performance improvement was obtained when the prediction was informed by 3D-context information.</p> <p>Conclusion</p> <p>While local one-dimensional amino acid sequence information was observed to harbor most of the discriminatory power, spatial context information was identified as relevant for the recognition of kinases and their cognate target sites and can be used for an improved prediction of phosphorylation sites. A web-based service (Phos3D) implementing the developed structure-based P-site prediction method has been made available at <url>http://phos3d.mpimp-golm.mpg.de</url>.</p

Computational approaches to predict protein functional families and functional sites.

Understanding the mechanisms of protein function is indispensable for many biological applications, such as protein engineering and drug design. However, experimental annotations are sparse, and therefore, theoretical strategies are needed to fill the gap. Here, we present the latest developments in building functional subclassifications of protein superfamilies and using evolutionary conservation to detect functional determinants, for example, catalytic-, binding- and specificity-determining residues important for delineating the functional families. We also briefly review other features exploited for functional site detection and new machine learning strategies for combining multiple features

A study of intrinsic disorder and its role in functional proteomics

Thesis (Ph.D.) - Indiana University, Informatics, 2009The last decade has witnessed the emergence of an alternate view on how protein function arises. This view attributes the functionality of many proteins to the presence of an ensemble of flexible regions popularly as `intrinsically disordered' or `unstructured'. Several proteomic studies have corroborated the existence of either wholly disordered proteins or proteins that contain regions of disorder in them. The purpose of this dissertation was to investigate the consistency of such regions across experiments, their mechanism of facilitating function via disorder-to-order transitions, their presence and significance in pathogenic versus non-pathogenic organisms and their promise of applicability towards the computational prediction of peptides involved in the most common class of post-translational modifications, phosphorylation. Besides these, a new algorithm exploiting the strong correlation between phosphorylation and intrinsic disorder has also been proposed to improve the detection of phosphorylated peptides via high-throughput methods such as tandem mass-spectrometry (LC-MS/MS). Results presented in this study, guide us in understanding the robustness of unstructured regions in proteins to sequence changes and environment, their role in facilitating molecular recognition as well as improving currently available methods for identification of post-translationally modified peptides. The findings and conclusions of this dissertation have the potential to impact ongoing structural genomics initiatives by suggesting alternative methods for determining structure for targets containing regions of disorder. Additional ramifications of results from this work include directing attention towards the possible use of regions of intrinsic disorder by pathogenic organisms for host cell invasion. We believe that unlike the traditional reductionist approach in a scientific method, this study gathers strength and utility by investigating the role of intrinsic disorder on more than one front in order to provide a novel perspective to the understanding of complex interactions within biological systems. Concluding arguments presented in this study pique one's curiosity regarding the evolution of disordered regions and proteins in general. On a technological side, the findings from this study unequivocally support the viable use of informatics methods in gaining new insights about a relatively young class of proteins known as intrinsically disordered proteins and its applicability to improve our present knowledge of cellular physiology

Multidimensional Feature Engineering for Post-Translational Modification Prediction Problems

Protein sequence data has been produced at an astounding speed. This creates an opportunity to characterize these proteins for the treatment of illness. A crucial characterization of proteins is their post translational modifications (PTM). There are 20 amino acids coded by DNA after coding (translation) nearly every protein is modified at an amino acid level. We focus on three specific PTMs. First is the bonding formed between two cysteine amino acids, thus introducing a loop to the straight chain of a protein. Second, we predict which cysteines can generally be modified (oxidized). Finally, we predict which lysine amino acids are modified by the active form of Vitamin B6 (PLP/pyridoxal-5-phosphate.) Our work aims to predict the PTM\u27s from protein sequencing data. When available, we integrate other data sources to improve prediction. Data mining finds patterns in data and uses these patterns to give a confidence score to unknown PTMs. There are many steps to data mining; however, our focus is on the feature engineering step i.e. the transforming of raw data into an intelligible form for a prediction algorithm. Our primary innovation is as follows: First, we created the Local Similarity Matrix (LSM), a description of the evolutionarily relatedness of a cysteine and its neighboring amino acids. This feature is taken two at a time and template matched to other cysteine pairs. If they are similar, then we give a high probability of it sharing the same bonding state. LSM is a three step algorithm, 1) a matrix of amino acid probabilities is created for each cysteine and its neighbors from an alignment. 2) We multiply the iv square of the BLOSUM62 matrix diagonal to each of the corresponding amino acids. 3) We z-score normalize the matrix by row. Next, we innovated the Residue Adjacency Matrix (RAM) for sequential and 3-D space (integration of protein coordinate data). This matrix describes cysteine\u27s neighbors but at much greater distances than most algorithms. It is particularly effective at finding conserved residues that are further away while still remaining a compact description. More data than necessary incurs the curse of dimensionality. RAM runs in O(n) time, making it very useful for large datasets. Finally, we produced the Windowed Alignment Scoring algorithm (WAS). This is a vector of protein window alignment bit scores. The alignments are one to all. Then we apply dimensionality reduction for gains in speed and performance. WAS uses the BLAST algorithm to align sequences within a window surrounding potential PTMs, in this case PLP attached to Lysine. In the case of WAS, we tried many alignment algorithms and used the approximation that BLAST provides to reduce computational time from months to days. The performances of different alignment algorithms did not vary significantly. The applications of this work are many. It has been shown that cysteine bonding configurations play a critical role in the folding of proteins. Solving the protein folding problem will help us to find the solution to Alzheimer\u27s disease that is due to a misfolding of the amyloid-beta protein. Cysteine oxidation has been shown to play a role in oxidative stress, a situation when free radicals become too abundant in the body. Oxidative stress leads to chronic illness such as diabetes, cancer, heart disease and Parkinson\u27s. Lysine in concert with PLP catalyzes the aminotransferase reaction. Research suggests that anti-cancer drugs will potentially selectively inhibit this reaction. Others have targeted this reaction for the treatment of epilepsy and addictions