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Partition function estimation in computational protein design with continuous-label Markov random fields

dc.contributor.advisor Donald, Bruce Randall
dc.contributor.author Mukund, Aditya
dc.date.accessioned 2017-05-04T17:13:09Z
dc.date.available 2019-05-04T08:17:12Z
dc.date.issued 2017-05-04
dc.identifier.uri https://hdl.handle.net/10161/14261
dc.description.abstract Proteins perform a variety of biological tasks, and drive many of the dynamic processes that make life possible. Computational structure-based protein design (CSPD) involves computing optimal sequences of amino acids with respect to particular backbones, or folds, in order to produce proteins with novel functions. In particular, it is crucial to be able to accurately model protein-protein interfaces (PPIs) in order to realize desired functionalities. Accurate modeling of PPIs raises two significant considerations. First, incorporating continuous side-chain flexibility in the design process has been shown to significantly improve the quality of designs. Second, because proteins exist as ensembles of structures, many of the properties we wish to design, including binding affinity, require the computation of ensemble properties as opposed to features of particular conformations. The bottleneck in many design algorithms that attempt to handle the ensemble nature of protein structure, including the Donald Lab’s K ∗ algorithm, is the computation of the partition function, which is the sum of the Boltzmann-weighted energies of all the conformational states of a protein or protein-ligand complex. Protein design can be formulated as an inference problem on Markov random fields (MRFs), where each residue to be designed is represented by a node in the MRF and an edge is placed between nodes corresponding to interacting residues. Label sets on each vertex correspond to allowed flexibility in the underlying design problem. The aim of this work is to extend message-passing algorithms that estimate the partition function for Markov random fields with discrete label sets to MRFs with continuous label sets in order to compute the partition function for PPIs with continuous flexibility and continuous entropy.
dc.language.iso en_US
dc.subject protein design
dc.subject markov random fields
dc.subject variational inference
dc.subject reproducing kernel hilbert spaces
dc.subject partition function
dc.title Partition function estimation in computational protein design with continuous-label Markov random fields
dc.type Honors thesis
dc.department Computer Science
duke.embargo.months 24


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