Method for generating information related to the molecular structure of a biomolecule

A method for generating a model of the molecular structure of a biomolecule and information related to the said molecular structure, the method being executable by a computer under the control of a program stored in the computer, and comprising the steps of:

• (a) receiving a representation of a molecular structure of said biomolecule comprising a plurality of residue portions, and forming from the plurality of residue portions a first set of residue portions, the remainder of the molecular structure being designated as a template;
• (b) defining an energetic cost function which assigns a quantitative energetic cost to any global structure of the said biomolecule and to any set of residue portions thereof;
• (c) providing a set of rotamers for each residue portion of the first set of residue portions formed in step (a) wherein each rotamer is fixed in a rotameric state;
• (d) assigning one rotamer from the set of rotamers of step (c) to each residue portion of the first set formed in step (a), thereby defining a first current global structure for said biomolecule;
• wherein the method further comprises modifying said first current global structure by repeating an optimization cycle, wherein each optimization cycle comprises the following steps (e) through (i):
• (e) providing, from the first set of residue portions with assigned rotamer states of step (d), a second set of residue portions wherein the second set of residue portions have been perturbed and then temporarily fixed in a rotameric state selected from those provided in step (c);
• and providing, from the first set of residue portions with assigned rotamer states of step (d), a third set of residue portions that have not been perturbed;
• (f) relaxing each residue portion of the third set towards an energetically more optimal state by:
• (f1) considering at least some rotamers of the set of step (c);
• (f2) calculating, for each considered rotamer, while using the energetic cost function of step (b), its individual contribution to the energetic cost of the global structure consisting of the template, the one or more residue portions of the second set in their temporarily fixed rotameric states, the residue portions of the third set, and the remaining residue portions of the first set, if any, in their assigned rotameric states, and
• (f3) selecting, from the rotamers considered in step (f1), the rotamer with the most optimal individual contributions calculated in step (f2);
• (g) calculating, using the energetic cost function of step (b), the cost of the global structure consisting of the template, the one or more residue portions of the second set in their temporarily fixed rotameric states, the one or more residue portions of the third set in their rotameric states selected in step (f3), and the remaining residue portions of the first set, if any, in their assigned rotameric states;
• (h) defining a second current global structure by
• (h1) establishing a first acceptance criterion by comparing the global cost calculated in step (g) with the global cost, calculated using the energetic cost function of step (b), of the first current global structure of step (d), and
• (h2) if said first acceptance criterion is met, assigning by way of replacement, for each residue portion of the second set, the currently assigned rotamer with the rotamer temporarily fixed in step (e) and, for each residue portion of the third set, the currently assigned rotamer with the rotamer selected in step (f3);
• and
• (i) determining whether a predetermined termination criterion has been reached, wherein, if said predetermined termination criterion has been reached, said optimization cycle is terminated;
• and wherein the method further comprises:
• (j) outputting to a display or to a user in a user-readable format, a representation of a second current global structure defined in step (h) or the global cost calculated in step (g).