Claims
- 1. A method for selecting a molecule for a population which comprises:
a) selecting a first molecule with a conformation characterized by a particular set of coordinates that define the position of each atom in the first molecule; b) determining the energy of the first molecule; c) transforming the coordinates of the first molecule to the coordinates of a second structurally distinct molecule to produce a particular conformation of the second molecule characterized by a particular set of coordinates that define the position of each atom in the second molecule; d) determining the energy of the second molecule, thus selecting either the first molecule or the second molecule for the population based on their relative energies.
- 2. The method of claim 1, wherein the method is repeated iteratively so as to generate a population of selected first molecules and a population of selected second molecules.
- 3. The method of claim 1, wherein the method is repeated iteratively so as to generate a stable population of selected first molecules and a stable population of selected second molecules.
- 4. The method of claim 3, wherein the free energy difference between the first molecule and the second molecule is determined from the stable population of selected first molecules and the stable population of selected second molecules.
- 5. The method of claim 4, wherein either the first molecule or the second molecule is chosen based on the free energy difference between the first molecule and the second molecule.
- 6. The method of claim 1, wherein determining the energy of the first molecule or the second molecule is via molecular mechanics, semi-empirical methods or quantum mechanics.
- 7. The method of claim 1, wherein selecting either the first molecule or the second molecule based on their relative energies comprises a Boltzmann calculation, a probability calculation, a Metropolis transition probability calculation or a Monte Carlo calculation.
- 8. The method of claim 1, wherein either the first molecule or the second molecule or both molecules are subjected to extrinsic forces from an environment which is either a solvent or a vacuum.
- 9. The method of claim 1, wherein either the first molecule or the second molecule or both molecules are subjected to extrinsic forces from an environment which is defined by a continuum model for solvation.
- 10. The method of claim 1, wherein either the first molecule or the second molecule or both molecules are subjected to extrinsic forces from an environment containing a third molecule or molecules.
- 11. The method of claim 10, wherein the third molecule or molecules is water, an organic solvent, a biopolymer, a bio-oligomer, a protein, an enzyme, a peptide, a nucleic acid, a carbohydrate, a glycoprotein, a receptor, a lipid bilayer, a bio-compatible polymer, a metal, an organic compound, an inorganic compound, a natural product, a pharmaceutical compound, a drug or a drug candidate.
- 12. The method of claim 1, wherein the coordinates are external or internal coordinates.
- 13. The method of claim 12, wherein the external coordinates are Cartesian coordinates.
- 14. The method of claim 12, wherein the internal coordinates include bond lengths, bond angles or torsion angles.
- 15. The method of claim 1, wherein the coordinates of the first molecule are transformed systematically, randomly, or systematically and randomly to produce the conformation of the second molecule.
- 16. The method of claim 1, wherein the coordinates of the first molecule are systematically modified so as to produce the conformation of the second molecule, which conformation is relatively low in energy.
- 17. The method of claim 1, wherein the coordinates of the first molecule are transformed to produce the coordinates of the second molecule with randomization of one or more of the coordinates of the first molecule.
- 18. The method of claim 1, wherein the coordinates of the first molecule or the coordinates of the second molecule are modified randomly or systematically.
- 19. The method of claim 1, wherein the coordinates of the first molecule or the coordinates of the second molecule are modified by molecular, stochastic, Langevin or Brownian dynamics.
- 20. The method of claim 1, wherein dummy atoms are used to represent atoms that are absent in the first molecule but present in the second molecule, or present in the first molecule but absent in the second molecule.
- 21. The method of claim 1, wherein the first molecule or the second molecule is a biopolymer, a bio-oligomer, a protein, an enzyme, a peptide, a nucleic acid, a carbohydrate, a glycoprotein, a receptor, an organic compound, an inorganic compound, a natural product, a pharmaceutical compound, a drug or a drug candidate, an agrochemical, a herbicide, an insecticide or a component of a chromatography medium.
- 22. The method of claim 4, wherein the free energy difference is calculated by a computer which processes data representing the physical or energetic characteristics of first molecule and the second molecule and conformations thereof.
- 23. The method of claim 1, wherein the method is used to select a candidate for a drug, an agrochemical, a synthetic receptor or a catalyst.
- 24. A method for predicting a relative binding free energy between a first molecule and a second molecule each for a third molecule which comprises using the method of claim 1 with the first molecule free and the second molecule free and with the first molecule and the second molecule interacting with the third molecule or environment.
- 25. The method of claim 24, wherein the method is performed by a computer which computer processes data which represents the physical or energetic characteristics of the first molecule free and the first molecule interacting with the third molecule and of the second molecule free and the second molecule interacting with the third molecule.
- 26. An apparatus for selecting molecules for a population which comprises:
a) a means of selecting a first molecule with a conformation characterized by a particular set of coordinates that define the position of each atom in the first molecule; b) a means of determining the energy of the first molecule; c) a means of transforming the coordinates of the first molecule to the coordinates of a second structurally distinct molecule to produce a particular conformation of the second molecule characterized by a particular set of coordinates that define the position of each atom in the second molecule; d) a means of determining the energy of the second molecule; thus, selecting either the first molecule or the second molecule based on their relative energies.
- 27. The apparatus of claim 26, wherein the steps are repeated iteratively so as to generate a population of selected first molecules and a population of selected second molecules.
- 28. The apparatus of claim 26, wherein the steps are repeated iteratively so as to generate a stable population of selected first molecules and a stable population of selected second molecules.
- 29. The apparatus of claim 28, wherein the free energy difference between the first molecule and the second molecule is determined from the stable population of selected first molecules and the stable population of selected second molecules.
- 30. The apparatus of claim 29, wherein either the first molecule or the second molecule is chosen based on the free energy difference between the first molecule and the second molecule.
Government Interests
[0001] The invention disclosed herein was made with Government support under Grant No. CHE 92-08254 from the National Science Foundation. Accordingly, the U.S. Government has certain rights in this invention.