The theoretical limits of DNA sequence discrimination by linked polyamides

Walker, Wynn L.; Landaw, Elliot M.; Dickerson, Richard E.; Goodsell, David S.

doi:10.1073/pnas.95.8.4315

Cited by 6 publications

(1 citation statement)

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“…Specifically, we address optimal strategies for designing a DNA sequence reading polyamide to maximize its specificity for a given target DNA sequence, given a limited repertoire of building blocks for the polyamide drug. In Walker et al (1998) we demonstrated without proof several features of the optimal design of linked polyamides. In this paper we generalize the results by presenting formal machinery and proofs for characterizing the theoretical limits of the DNA sequence specificity of hypothetical sequence reading molecules as a function of their base recognition properties and the sequence content of their target sequence.…”

Section: Introductionmentioning

confidence: 97%

An Analysis of a Class of DNA Sequence Reading Molecules

Walker¹,

Goodsell²,

Landaw

1998

Journal of Computational Biology

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Linked polyamides are a class of designed molecules that bind in the minor groove of double-stranded DNA in a partially sequence-specific manner but have limited sequence discriminatory abilities. This suggests a need for design alternatives to create molecules with enhanced sequence specificity. In this report we present formal proofs of the theoretical limits of the DNA sequence specificity of hypothetical sequence reading molecules as a function of their base recognition properties and sequence content and length of their target sequence. We prove that molecules containing nonspecific readers at critical positions within the molecule may have enhanced sequence specificity over molecules composed entirely of base specific reading elements. We also determine optimal patterns of base recognition for molecules in order to optimize their target sequence specificity. We also examine the effect of the length of a polyamide (i.e., the number of base pairs it binds) on its sequence discriminatory ability and determine necessary concentration dependent constraints on the binding free energies in order for longer polyamides to have greater sequence specificity than shorter ones. We show that unless the discriminatory ability of a ring for its preferred base is very strong, longer polyamides do not necessarily have greater sequence specificity over shorter ones when compared at the same molar concentration.

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Section: Introductionmentioning

confidence: 97%

An Analysis of a Class of DNA Sequence Reading Molecules

Walker¹,

Goodsell²,

Landaw

1998

Journal of Computational Biology

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Progress in the design of DNA sequence-specific lexitropsins

Walker¹,

Kopka²,

Goodsell³

1997

Biopolymers

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Sequence‐specific polyamides that bind in the minor groove of DNA are attractive candidates for antibiotics, cancer chemotherapeutics, and transcriptional antagonists. This paper reviews the progress of structure‐based design of minor‐groove‐binding polyamides, from the first structure of netropsin with DNA, to the effective linked polyamides currently under study. A theory of polyamide specificity is also reviewed, introducing methods to determine the optimal strategies for targeting a given DNA sequence within a genome of competing sequences. © 1998 John Wiley & Sons, Inc. Biopoly 44: 323–334, 1997

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