A Deterministic Optimization Approach to Protein Sequence Design Using Continuous Models

Koh, Sung K and Ananthasuresh, GK and Vishveshwara , S (2005) A Deterministic Optimization Approach to Protein Sequence Design Using Continuous Models. In: The International Journal of Robotics , 24 (2-3). pp. 109-130.

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Abstract

Determining the sequence of amino acid residues in a heteropolymer chain of a protein with a given conformation is a discrete combinatorial problem that is not generally amenable for gradient-based continuous optimization algorithms. In this paper we present a new approach to this problem using continuous models. In this modeling, continuous "state functions" are proposed to designate the type of each residue in the chain. Such a continuous model helps define a continuous sequence space in which a chosen criterion is optimized to find the most appropriate sequence. Searching a continuous sequence space using a deterministic optimization algorithm makes it possible to find the optimal sequences with much less computation than many other approaches. The computational efficiency of this method is further improved by combining it with a graph spectral method, which explicitly takes into account the topology of the desired conformation and also helps make the combined method more robust. The continuous modeling used here appears to have additional advantages in mimicking the folding pathways and in creating the energy landscapes that help find sequences with high stability and kinetic accessibility. To illustrate the new approach, a widely used simplifying assumption is made by considering only two types of residues: hydrophobic (H) and polar (P). Self-avoiding compact lattice models are used to validate the method with known results in the literature and data that can be practically obtained by exhaustive enumeration on a desktop computer. We also present examples of sequence design for the HP models of some real proteins, which are solved in less than five minutes on a single-processor desktop computer Some open issues and future extensions are noted.

Item Type:	Journal Article
Publication:	The International Journal of Robotics
Publisher:	Sage Publications
Additional Information:	Copyright of this article belongs to Sage Publications.
Keywords:	protein sequence design, deterministic optimization, inverse folding, lattice models, and graph spectral method.
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit Division of Mechanical Sciences > Mechanical Engineering
Date Deposited:	14 Dec 2010 05:49
Last Modified:	14 Dec 2010 05:49
URI:	http://eprints.iisc.ac.in/id/eprint/34364

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