Publications by authors named "William Krivan"

5 Publications

  • Page 1 of 1

Flexgrepps--flexible greedy peptide pool search: computation of near-optimal sets of degenerate polypeptides for antigenic screening.

J Bioinform Comput Biol 2012 Oct 22;10(5):1250009. Epub 2012 Jun 22.

Protein Advances, Inc.-Protein AI, 1102 Columbia Street, Suite 110, Seattle, Washington 98104, USA.

Although synthesizing and utilizing individual peptides and DNA primers has become relatively inexpensive, massively parallel probing and next-generation sequencing approaches have dramatically increased the number of molecules that can be subjected to screening; this, in turn, requires vast numbers of peptides and therefore results in significant expenses. To alleviate this issue, pools of related molecules are often used to downselect prior to testing individual sequences. A computational selection process to create pools of related sequences at large scale has not been reported for peptides. In the case of PCR primers, there have been successful attempts to address this problem by designing degenerate primers that can be produced at the same cost as conventional, unique primers and then be used to amplify several different genomic regions. We present an algorithm, "FlexGrePPS" (Flexible Greedy Peptide Pool Search), that can create a near-optimal set of peptide pools. This approach is also applicable to nucleotide sequences and outperforms most DNA primer selection programs. For the proteomic compression with FlexGrePPS, the main body of our work presented here, we demonstrate the feasibility of the computation of an exhaustive cover of pathogenic proteomes with degenerate peptides that lend themselves to antigenic screening. Furthermore, we present preliminary data that demonstrate the experimental utility of highly degenerate peptides for antigenic screening. FlexGrePPS provides a near-optimal solution for proteomic compression and there are no programs available for comparison. We also demonstrate computational performance of our GreedyPrime implementation, which is a modified version of FlexGrePPS applicable to the design of degenerate primers and is comparable to existing programs for the design of degenerate primers. Specifically, we focus on the comparisons with PAMPS and DPS-DIP, software tools that have recently been shown to be superior to other methods. FlexGrePPS forms the foundation of a novel antigenic screening methodology that is based on the representation of an entire proteome by near-optimal degenerate peptide pools. Our preliminary wet lab data indicate that the approach will likely prove successful in comprehensive wet lab studies, and hence will dramatically reduce the expenses for antigenic screening and make whole proteome screening feasible. Although FlexGrePPS was designed for computational performance in order to handle vast data sets, there is the very surprising finding that even for small data sets the primer design version of FlexGrePPS, GreedyPrime, offers similar or even superior results for MP-DPD and most MDPD instances when compared to existing methods; despite the much longer run times, other approaches did not fare significantly better in reducing the original data sets to degenerate primers. The FlexGrePPS and GreedyPrime programs are available at no charge under the GNU LGPL license at http://sourceforge.net/projects/flexgrepps/.
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http://dx.doi.org/10.1142/S0219720012500096DOI Listing
October 2012

Exploring the protein landscape in ramachandran space: it's not just psi-phi.

J Bioinform Comput Biol 2009 Dec;7(6):1031-7

Protein Advances, Inc., Seattle, Washington 98104, USA.

Most methods for the structural comparison of proteins utilize molecular coordinates in the three-dimensional physical space. Recently, a group has presented an elegant novel approach based on the characterization of protein shape in terms of backbone torsion angles. They have demonstrated considerable success in direct comparisons with other techniques, and their method lends itself to rapid screening of structural information from rapidly growing databases. We think that the torsion angle approach can be further strengthened by refining the distance notion that forms the basis of the computational scheme. In particular, we are suggesting to compute the distance along the path that minimizes the transition cost between aligned pairs of angles and therefore likely provides a more meaningful representation of distances between points in Ramachandran space.
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http://dx.doi.org/10.1142/s0219720009004400DOI Listing
December 2009

Searching for transcription factor binding site clusters: how true are true positives?

Authors:
William Krivan

J Bioinform Comput Biol 2004 Jun;2(2):413-6

ZymoGenetics, Inc., 1201 Eastlake Avenue East, Seattle, Washington 98102, USA.

The computational detection of functional transcription factor binding sites in genomic sequence is one of the challenges of the post-genomic era. Several groups have approached this problem from different directions and have demonstrated considerable success. The purpose of this communication, however, is to point out an imperfection in the way computational results are commonly reported that may lead to a distorted picture of the performance of existing algorithms.
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http://dx.doi.org/10.1142/s021972000400065xDOI Listing
June 2004

In silico identification of metazoan transcriptional regulatory regions.

Naturwissenschaften 2003 Apr 27;90(4):156-66. Epub 2003 Mar 27.

Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.

Transcriptional regulation remains one of the most intriguing and challenging subjects in biomedical research. The catalysis of transcription is a clear example of multiple proteins interacting to orchestrate a biological process, offering a starting point for the study of biological systems. Transcriptional regulation is viewed as one of the principal mechanisms governing the spatial and temporal distribution of gene expression, thus the field of transcriptional regulation provides a natural stage for quantitative studies of multiple gene systems. Building on the body of focused experimental studies and new genomics-driven data, computational biologists are making significant strides in accelerating our understanding of the transcriptional regulatory process in metazoan cells. Recent advances in the computational analysis of the interplay between factors have been fueled by well-defined computational methods for the modeling of the binding of individual transcription factors. We present here an overview of advances in the analysis of regulatory systems and the fundamental methods that underlie the recent developments.
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http://dx.doi.org/10.1007/s00114-003-0409-4DOI Listing
April 2003

IL-28, IL-29 and their class II cytokine receptor IL-28R.

Nat Immunol 2003 Jan 2;4(1):63-8. Epub 2002 Dec 2.

ZymoGenetics, Inc., 1201 Eastlake Avenue E., Seattle, WA 98102, USA.

Cytokines play a critical role in modulating the innate and adaptive immune systems. Here, we have identified from the human genomic sequence a family of three cytokines, designated interleukin 28A (IL-28A), IL-28B and IL-29, that are distantly related to type I interferons (IFNs) and the IL-10 family. We found that like type I IFNs, IL-28 and IL-29 were induced by viral infection and showed antiviral activity. However, IL-28 and IL-29 interacted with a heterodimeric class II cytokine receptor that consisted of IL-10 receptor beta (IL-10Rbeta) and an orphan class II receptor chain, designated IL-28Ralpha. This newly described cytokine family may serve as an alternative to type I IFNs in providing immunity to viral infection.
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http://dx.doi.org/10.1038/ni873DOI Listing
January 2003