Enriching Peptide Libraries for Binding Affinity and Specificity Through Computationally Directed Library Design

Peptide reagents with high affinity or specificity for their target protein interaction partner are of utility for many important applications. Optimization of peptide binding by screening large libraries is a proven and powerful approach. Libraries designed to be enriched in peptide sequences that are predicted to have desired affinity or specificity characteristics are more likely to yield success than random mutagenesis. We present a library optimization method in which the choice of amino acids to encode at each peptide position can be guided by available experimental data or structure-based predictions. We discuss how to use analysis of predicted library performance to inform rounds of library design. Finally, we include protocols for more complex library design procedures that consider the chemical diversity of the amino acids at each peptide position and optimize a library score based on a user-specified input model.National Institute of General Medical Sciences (U.S.) (Award R01 GM110048

Effect of the Side Effect Machines in Edit Metric Decoding

The development of general edit metric decoders is a challenging problem, especially with the inclusion of additional biological restrictions that can occur in DNA error correcting codes. Side effect machines (SEMs), an extension of finite state machines, can provide efficient decoding algorithms for such edit metric codes. However, finding a good machine poses its own set of challenges and is itself considered as an open problem with no general solution. Previous studies utilizing evolutionary computation techniques, such as genetic algorithms and evolutionary programming to search for good SEMs have found success in terms of decoding accuracy. However, they all worked with extremely constricted problem spaces i.e. a single code or codes of the same length. Therefore a general approach that works well across codes of different lengths is yet to be formalized. In this research, several codes of varying lengths are used to study the effectiveness of evolutionary programming (EP) as a general approach for finding efficient edit metric decoders. Two classification methods—direct and fuzzy—are compared while also changing some of the EP settings to observe how the decoding accuracy is affected. The final SEMs are verified against an additional dataset to test their general effectiveness. Regardless of the code length, the best results are found using the fuzzy classification methods. For codes of length 10, a maximum accuracy of up to 99.4% is achieved for distance 1 whereas distance 2 and 3 achieve up to 97.1% and 85.9%, respectively. Unsurprisingly, the accuracy suffers for longer codes, as the maximum accuracies achieved by codes of length 14 were 92.4%, 85.7% and 69.2% for distance 1, 2, and 3 respectively. Additionally, the machines are examined for potential bloat by comparing the number of visited states against the number of total states. The study has found some machines with at least one unvisited state. The bloat is seen more in larger machines than it is in smaller machines. Furthermore, the results are analyzed to find potential trends and relationships among the parameters. The trend that is most consistently noticed is that — when allowed, the longer codes generally show a propensity for larger machines

Chemistry-informed Macromolecule Graph Representation for Similarity Computation and Supervised Learning

Macromolecules are large, complex molecules composed of covalently bonded monomer units, existing in different stereochemical configurations and topologies. As a result of such chemical diversity, representing, comparing, and learning over macromolecules emerge as critical challenges. To address this, we developed a macromolecule graph representation, with monomers and bonds as nodes and edges, respectively. We captured the inherent chemistry of the macromolecule by using molecular fingerprints for node and edge attributes. For the first time, we demonstrated computation of chemical similarity between 2 macromolecules of varying chemistry and topology, using exact graph edit distances and graph kernels. We also trained graph neural networks for a variety of glycan classification tasks, achieving state-of-the-art results. Our work has two-fold implications - it provides a general framework for representation, comparison, and learning of macromolecules; and enables quantitative chemistry-informed decision-making and iterative design in the macromolecular chemical space.Comment: Main text: 4 pages, 2 figures, 1 table; Appendix: 18 pages, 25 figures, 3 table

Integrated multiple sequence alignment

Sammeth M. Integrated multiple sequence alignment. Bielefeld (Germany): Bielefeld University; 2005.The thesis presents enhancements for automated and manual multiple sequence alignment: existing alignment algorithms are made more easily accessible and new algorithms are designed for difficult cases. Firstly, we introduce the QAlign framework, a graphical user interface for multiple sequence alignment. It comprises several state-of-the-art algorithms and supports their parameters by convenient dialogs. An alignment viewer with guided editing functionality can also highlight or print regions of the alignment. Also phylogenetic features are provided, e.g., distance-based tree reconstruction methods, corrections for multiple substitutions and a tree viewer. The modular concept and the platform-independent implementation guarantee an easy extensibility. Further, we develop a constrained version of the divide-and-conquer alignment such that it can be restricted by anchors found earlier with local alignments. It can be shown that this method shares attributes of both, local and global aligners, in the quality of results as well as in the computation time. We further modify the local alignment step to work on bipartite (or even multipartite) sets for sequences where repeats overshadow valuable sequence information. In the end a technique is established that can accurately align sequences containing eventually repeated motifs. Finally, another algorithm is presented that allows to compare tandem repeat sequences by aligning them with respect to their possible repeat histories. We describe an evolutionary model including tandem duplications and excisions, and give an exact algorithm to compare two sequences under this model

Multiple Biolgical Sequence Alignment: Scoring Functions, Algorithms, and Evaluations

Aligning multiple biological sequences such as protein sequences or DNA/RNA sequences is a fundamental task in bioinformatics and sequence analysis. These alignments may contain invaluable information that scientists need to predict the sequences\u27 structures, determine the evolutionary relationships between them, or discover drug-like compounds that can bind to the sequences. Unfortunately, multiple sequence alignment (MSA) is NP-Complete. In addition, the lack of a reliable scoring method makes it very hard to align the sequences reliably and to evaluate the alignment outcomes. In this dissertation, we have designed a new scoring method for use in multiple sequence alignment. Our scoring method encapsulates stereo-chemical properties of sequence residues and their substitution probabilities into a tree-structure scoring scheme. This new technique provides a reliable scoring scheme with low computational complexity. In addition to the new scoring scheme, we have designed an overlapping sequence clustering algorithm to use in our new three multiple sequence alignment algorithms. One of our alignment algorithms uses a dynamic weighted guidance tree to perform multiple sequence alignment in progressive fashion. The use of dynamic weighted tree allows errors in the early alignment stages to be corrected in the subsequence stages. Other two algorithms utilize sequence knowledge-bases and sequence consistency to produce biological meaningful sequence alignments. To improve the speed of the multiple sequence alignment, we have developed a parallel algorithm that can be deployed on reconfigurable computer models. Analytically, our parallel algorithm is the fastest progressive multiple sequence alignment algorithm

Approximate string matching methods for duplicate detection and clustering tasks

Approximate string matching methods are utilized by a vast number of duplicate detection and clustering applications in various knowledge domains. The application area is expected to grow due to the recent significant increase in the amount of digital data and knowledge sources. Despite the large number of existing string similarity metrics, there is a need for more precise approximate string matching methods to improve the efficiency of computer-driven data processing, thus decreasing labor-intensive human involvement. This work introduces a family of novel string similarity methods, which outperform a number of effective well-known and widely used string similarity functions. The new algorithms are designed to overcome the most common problem of the existing methods which is the lack of context sensitivity. In this evaluation, the Longest Approximately Common Prefix (LACP) method achieved the highest values of average precision and maximum F1 on three out of four medical informatics datasets used. The LACP demonstrated the lowest execution time ensured by the linear computational complexity within the set of evaluated algorithms. An online interactive spell checker of biomedical terms was developed based on the LACP method. The main goal of the spell checker was to evaluate the LACP method’s ability to make it possible to estimate the similarity of resulting sets at a glance. The Shortest Path Edit Distance (SPED) outperformed all evaluated similarity functions and gained the highest possible values of the average precision and maximum F1 measures on the bioinformatics datasets. The SPED design was inspired by the preceding work on the Markov Random Field Edit Distance (MRFED). The SPED eradicates two shortcomings of the MRFED, which are prolonged execution time and moderate performance. Four modifications of the Histogram Difference (HD) method demonstrated the best performance on the majority of the life and social sciences data sources used in the experiments. The modifications of the HD algorithm were achieved using several re- scorers: HD with Normalized Smith-Waterman Re-scorer, HD with TFIDF and Jaccard re-scorers, HD with the Longest Common Prefix and TFIDF re-scorers, and HD with the Unweighted Longest Common Prefix Re-scorer. Another contribution of this dissertation includes the extensive analysis of the string similarity methods evaluation for duplicate detection and clustering tasks on the life and social sciences, bioinformatics, and medical informatics domains. The experimental results are illustrated with precision-recall charts and a number of tables presenting the average precision, maximum F1, and execution time