Statistical algorithms for folding and target accessibility prediction and design of nucleic acids
OwnerYe Ding, Charles E. Lawrenceinventors
Life of this patent
Estimating the term…
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.
Claims20
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.
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:
- 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.
A method of determining an antisense oligo of a predetermined length for an antisense nucleation site on a target RNA, comprising the steps of:
- 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.
A method of evaluating an antisense oligo for a target RNA, comprising the steps of:
- 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.
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:
- 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.
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:
- 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.
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:
- 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.
A computer program embodied on a computer-readable medium for evaluating an antisense oligo for a target RNA, comprising:
- 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.
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:
- 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.
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:
- 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.
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:
- 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.
A process embodied in an instruction signal of a computing device for evaluating an antisense oligo for a target RNA, comprising:
- 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.
Dependencies are inferred from the claim text.