Probabilistic protein homology modeling

Meier, Armin (2014): Probabilistic protein homology modeling. Dissertation, LMU München: Fakultät für Chemie und Pharmazie

Abstract

Searching sequence databases and building 3D models for proteins are important tasks for biologists. When the structure of a query protein is given, its function can be inferred. However, experimental methods for structure prediction are both expensive and time consuming. Fully automatic homology modeling refers to building a 3D model for a query sequence from an alignment to related homologous proteins with known structure (templates) by a computer. Current prediction servers can provide accurate models within a few hours to days. Our group has developed HHpred, which is one of the top performing structure prediction servers in the field. In general, homology based structure modeling consists of four steps: (1) finding homologous templates in a database, (2) selecting and (3) aligning templates to the query, (4) building a 3D model based on the alignment. In part one of this thesis, we will present improvements of step (2) and (4). Specifically, homology modeling has been shown to work best when multiple templates are selected instead of only a single one. Yet, current servers are using rather ad-hoc approaches to combine information from multiple templates. We provide a rigorous statistical framework for multi-template homology modeling. Given an alignment, we employ Modeller to calculate the most probable structure for a query. The 3D model is obtained by optimally satisfying spatial restraints derived from the alignment and expressed as probability density functions. We find that the query’s atomic distance restraints can be accurately described by two-component Gaussian mixtures. Moreover, we derive statistical weights to quantify the redundancy among related templates. This allows us to apply the standard rules of probability theory to combine restraints from several templates. Together with a heuristic template selection strategy, we have implemented this approach within HHpred and could significantly improve model quality. Furthermore, we took part in CASP, a community wide competition for structure prediction, where we were ranked first in template based modeling and, at the same time, were more than 450 times faster than all other top servers. Homology modeling heavily relies on detecting and correctly aligning templates to the query sequence (step (1) and (3) from above). But remote homologies are difficult to detect and hard to align on a pure sequence level. Hence, modern tools are based on profiles instead of sequences. A profile summarizes the evolutionary history of a given sequence and consists of position specific amino acid probabilities for each residue. In addition to the similarity score between profile columns, most methods use extra terms that compare 1D structural properties such as secondary structure or solvent accessibility. These can be predicted from local profile windows. In the second part of this thesis, we develop a new score that is independent of any predefined structural property. For this purpose, we learn a library of 32 profile patterns that are most conserved in alignments of remotely homologous, structurally aligned proteins. Each so called “context state” in the library consists of a 13-residue sequence profile. We integrate the new context score into our Hmm-Hmm alignment tool HHsearch and improve especially the sensitivity and precision of difficult pairwise alignments significantly. Taken together, we introduced probabilistic methods to improve all four main steps in homology based structure prediction.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 540 Chemie
• Fakultäten: Fakultät für Chemie und Pharmazie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 27. Juni 2014
• 1. Bericht­erstatter:in: Söding, Johannes