Dataset Information

ICFN: an efficient exact algorithm for multistate protein design.

ABSTRACT: Motivation:Multistate protein design addresses real-world challenges, such as multi-specificity design and backbone flexibility, by considering both positive and negative protein states with an ensemble of substates for each. It also presents an enormous challenge to exact algorithms that guarantee the optimal solutions and enable a direct test of mechanistic hypotheses behind models. However, efficient exact algorithms are lacking for multistate protein design. Results:We have developed an efficient exact algorithm called interconnected cost function networks (iCFN) for multistate protein design. Its generic formulation allows for a wide array of applications such as stability, affinity and specificity designs while addressing concerns such as global flexibility of protein backbones. iCFN treats each substate design as a weighted constraint satisfaction problem (WCSP) modeled through a CFN; and it solves the coupled WCSPs using novel bounds and a depth-first branch-and-bound search over a tree structure of sequences, substates, and conformations. When iCFN is applied to specificity design of a T-cell receptor, a problem of unprecedented size to exact methods, it drastically reduces search space and running time to make the problem tractable. Moreover, iCFN generates experimentally-agreeing receptor designs with improved accuracy compared with state-of-the-art methods, highlights the importance of modeling backbone flexibility in protein design, and reveals molecular mechanisms underlying binding specificity. Availability and implementation:https://shen-lab.github.io/software/iCFN. Supplementary information:Supplementary data are available at Bioinformatics online.

SUBMITTER: Karimi M

PROVIDER: S-EPMC6129278 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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iCFN: an efficient exact algorithm for multistate protein design.

Karimi Mostafa M Shen Yang Y

Bioinformatics (Oxford, England) 20180901 17

<h4>Motivation</h4>Multistate protein design addresses real-world challenges, such as multi-specificity design and backbone flexibility, by considering both positive and negative protein states with an ensemble of substates for each. It also presents an enormous challenge to exact algorithms that guarantee the optimal solutions and enable a direct test of mechanistic hypotheses behind models. However, efficient exact algorithms are lacking for multistate protein design.<h4>Results</h4>We have de ...[more]

PMID: 30423073

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Project description:MotivationThe motif discovery problem consists of finding over-represented patterns in a collection of biosequences. It is one of the classical sequence analysis problems, but still has not been satisfactorily solved in an exact and efficient manner. This is partly due to the large number of possibilities of defining the motif search space and the notion of over-representation. Even for well-defined formalizations, the problem is frequently solved in an ad hoc manner with heuristics that do not guarantee to find the best motif.ResultsWe show how to solve the motif discovery problem (almost) exactly on a practically relevant space of IUPAC generalized string patterns, using the p-value with respect to an i.i.d. model or a Markov model as the measure of over-representation. In particular, (i) we use a highly accurate compound Poisson approximation for the null distribution of the number of motif occurrences. We show how to compute the exact clump size distribution using a recently introduced device called probabilistic arithmetic automaton (PAA). (ii) We define two p-value scores for over-representation, the first one based on the total number of motif occurrences, the second one based on the number of sequences in a collection with at least one occurrence. (iii) We describe an algorithm to discover the optimal pattern with respect to either of the scores. The method exploits monotonicity properties of the compound Poisson approximation and is by orders of magnitude faster than exhaustive enumeration of IUPAC strings (11.8 h compared with an extrapolated runtime of 4.8 years). (iv) We justify the use of the proposed scores for motif discovery by showing our method to outperform other motif discovery algorithms (e.g. MEME, Weeder) on benchmark datasets. We also propose new motifs on Mycobacterium tuberculosis.Availability and implementationThe method has been implemented in Java. It can be obtained from http://ls11-www.cs.tu-dortmund.de/people/marschal/paa_md/.

Dataset Information

ICFN: an efficient exact algorithm for multistate protein design.

Publications

iCFN: an efficient exact algorithm for multistate protein design.

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