Statistical algorithms for folding and target accessibility prediction and design of nucleic acids
First Claim
1. A method of generating a sample of a predetermined number of probable secondary structures of an RNA sequence, comprising the steps of:
- a) generating one or more partition functions of a fragment having one or more bases of the RNA sequence in accordance with a predetermined number of thermodynamics parameters; and
b) generating secondary structures based on tracebacks using conditional probabilities computed with the partition function.
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Abstract
A method of predicting structural characteristics of a nucleic acid molecule. A method of predicting single-stranded regions in the secondary structure of a nucleic acid molecule in accordance with a probability distribution of structures based on recursively generated partition functions for the identification of accessible sites on target RNA for gene down-regulation and the rational design of antisense oligos, trans-cleaving ribozymes, siRNAss and antisense RNAs, for interaction with other RNA-targeting molecules, and for rational design of nucleic acid probes such as molecular beacons for RNA or DNA targets.
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Citations
20 Claims
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1. A method of generating a sample of a predetermined number of probable secondary structures of an RNA sequence, comprising the steps of:
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a) generating one or more partition functions of a fragment having one or more bases of the RNA sequence in accordance with a predetermined number of thermodynamics parameters; and
b) generating secondary structures based on tracebacks using conditional probabilities computed with the partition function. - View Dependent Claims (2, 3, 4, 17, 18, 19, 20)
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5. A method of generating a probability profile for predicting an accessible site on a target RNA for interaction with a biomolecule, comprising the steps of:
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a) generating a sample of one or more probable secondary structures of an RNA sequence by;
i) generating one or more partition functions of a fragment having one or more bases of the RNA sequence in accordance with a predetermined number of thermodynamics parameters, and ii) generating secondary structures based on tracebacks using conditional probabilities computed with the partition functions;
b) estimating a probability that a segment of one or more bases on the target RNA is single-stranded in accordance with an observed frequency in the sample; and
c) repeating the estimating step for all segments on the target RNA.
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6. A method of determining an antisense oligo of a predetermined length for an antisense nucleation site on a target RNA, comprising the steps of:
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a) generating a sample of one or more probable secondary structures of an RNA sequence by;
i) generating one or more partition functions of a fragment having one or more bases of the RNA sequence in accordance with a predetermined number of thermodynamics parameters, and ii) generating secondary structures based on tracebacks using conditional probabilities computed with the partition functions;
b) estimating a probability that a segment of one or more bases on the target RNA is single-stranded by using an observed frequency in the sample;
c) repeating the estimating step for all segments on the target RNA;
d) identifying a target segment in accordance with the estimated probabilities;
e) determining a base sequence of the target segment; and
f) determining the antisense oligo in accordance with the base sequence.
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7. A method of evaluating an antisense oligo for a target RNA, comprising the steps of:
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a) generating a sample of one or more probable secondary structures of an RNA sequence by;
i) generating one or more partition functions of a fragment having one or more bases of the RNA sequence in accordance with a predetermined number of thermodynamics parameters, and ii) generating secondary structures based on tracebacks using conditional probabilities computed with the partition functions;
b) estimating a probability that a segment of one or more bases on the target RNA is single-stranded in accordance with an observed frequency in the sample; and
c) repeating the estimating step for all segments on the target RNA;
d) calculating a sampling-probability-weighted binding energy for measuring a nucleation potential of a hybridization between the antisense oligo and the target RNA; and
e) generating an evaluation indicator for the antisense oligo in accordance with the sampling-probability-weighted binding energy and the estimated probabilities for the target RNA. - View Dependent Claims (8)
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9. A computer program embodied on a computer-readable medium for generating a sample of a predetermined number of probable secondary structures of an RNA sequence, comprising:
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a) an instruction for generating one or more partition functions of a fragment having one or more bases of the RNA sequence in accordance with a predetermined number of thermodynamics parameters; and
b) an instruction for generating secondary structures based on tracebacks using conditional probabilities computed with the partition function.
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10. A computer program embodied on a computer-readable medium for generating a probability profile for predicting an accessible site on a target RNA for interaction with a biomolecule, comprising:
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a) an instruction for generating a sample of one or more probable secondary structures of an RNA sequence by;
i) generating one or more partition functions of a fragment having one or more bases of the RNA sequence in accordance with a predetermined number of thermodynamics parameters, and ii) generating secondary structures based on tracebacks using conditional probabilities computed with the partition functions;
b) an instruction for estimating a probability that a segment of one or more bases on the target RNA is single-stranded in accordance with an observed frequency in the sample, wherein the estimating instruction is repeated for all segments on the target RNA.
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11. A computer program embodied on a computer-readable medium for determining an antisense oligo of a predetermined length for an antisense nucleation site on a target RNA, comprising:
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a) an instruction for generating a sample of one or more probable secondary structures of an RNA sequence by;
i) generating one or more partition functions of a fragment having one or more bases of the RNA sequence in accordance with a predetermined number of thermodynamics parameters, and ii) generating secondary structures based on tracebacks using conditional probabilities computed with the partition functions;
b) an instruction for estimating a probability that a segment of one or more bases on the target RNA is single-stranded by using an observed frequency in the sample, said estimating instruction being repeated for all segments on the target RNA;
c) an instruction for identifying a target segment in accordance with the estimated probabilities;
d) an instruction for determining a base sequence of the target segment; and
e) an instruction for determining the antisense oligo in accordance with the base sequence.
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12. A computer program embodied on a computer-readable medium for evaluating an antisense oligo for a target RNA, comprising:
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a) an instruction for generating a sample of one or more probable secondary structures of an RNA sequence by;
i) generating one or more partition functions of a fragment having one or more bases of the RNA sequence in accordance with a predetermined number of thermodynamics parameters, and ii) generating secondary structures based on tracebacks using conditional probabilities computed with the partition functions;
b) an instruction for estimating a probability that a segment of one or more bases on the target RNA is single-stranded in accordance with an observed frequency in the sample, said estimating instruction being repeated for all bases on the target RNA;
c) an instruction for calculating a sampling-probability-weighted free energy for measuring a nucleation potential of a hybridization between the antisense oligo and the target RNA; and
d) an instruction for generating an evaluation indicator for the antisense oligo in accordance with the sampling-probability-weighted binding energy and the estimated probabilities for the target RNA.
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13. A process embodied in an instruction signal of a computing device for generating a sample of a predetermined number of probable secondary structures of an RNA sequence, comprising:
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a) an instruction for generating one or more partition functions of a fragment having one or more bases of the RNA sequence in accordance with a predetermined number of thermodynamics parameters; and
b) an instruction for generating secondary structures based on tracebacks using conditional probabilities computed with the partition functions.
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14. A process embodied in an instruction signal of a computing device for generating a probability profile for predicting an accessible site on a target RNA for interaction with a biomolecule, comprising:
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a) an instruction for generating a sample of one or more probable secondary structures of an RNA sequence by;
i) generating one or more partition functions of a fragment having one or more bases of the RNA sequence in accordance with a predetermined number of thermodynamics parameters, and ii) generating secondary structures based on tracebacks using conditional probabilities computed with the partition functions;
b) an instruction for estimating a probability that a segment of one or more bases on the target RNA is single-stranded in accordance with an observed frequency in the sample, wherein the estimating instruction is repeated for all segments on the target RNA.
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15. A process embodied in an instruction signal of a computing device for determining an antisense oligo of a predetermined length for an antisense nucleation site on a target RNA, comprising:
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a) an instruction for generating a sample of one or more probable secondary structures of an RNA sequence by;
i) generating one or more partition functions of a fragment having one or more bases of the RNA sequence in accordance with a predetermined number of thermodynamics parameters, and ii) generating secondary structures based on tracebacks using conditional probabilities computed with the partition functions;
b) an instruction for estimating a probability that a segment of one or more bases on the target RNA is single-stranded by using an observed frequency in the sample, said estimating instruction being repeated for all segments on the target RNA;
c) an instruction for identifying a target segment in accordance with the estimated probabilities;
d) an instruction for determining a base sequence of the target segment; and
e) an instruction for determining the antisense oligo in accordance with the base sequence.
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16. A process embodied in an instruction signal of a computing device for evaluating an antisense oligo for a target RNA, comprising:
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a) an instruction for generating a sample of one or more probable secondary structures of an RNA sequence by;
i) generating one or more partition functions of a fragment having one or more bases of the RNA sequence in accordance with a predetermined number of thermodynamics parameters, and ii) generating secondary structures based on tracebacks using conditional probabilities computed with the partition functions;
b) an instruction for estimating a probability that a segment of one or more bases on the target RNA is single-stranded in accordance with an observed frequency in the sample, said estimating instruction being repeated for all segments on the target RNA;
c) an instruction for calculating a sampling-probability-weighted free energy for measuring a nucleation potential of a hybridization between the antisense oligo and the target RNA; and
d) an instruction for generating an evaluation indicator for the antisense oligo in accordance with the sampling-probability-weighted free energy and the estimated probabilities for the target RNA.
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Specification