Methods to identify macromolecule binding and aggregation prone regions in proteins and uses therefor
AssigneesMassachusetts Institute of Technology, Novartis AG
InventorsNaresh Chennamsetty, Bernhard Helk, Bernhardt Trout, Veysel Kayser, Vladimir Voynov
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Abstract
The present invention provides methods and computational tools based, at least in part, on computer simulations that identify macromolecule binding regions and aggregation prone regions of a protein. Substitutions may then be made in these aggregation prone regions to engineer proteins with enhanced stability and/or a reduced propensity for aggregation. Similarly, substitutions may then be made in these macromolecule binding regions to engineer proteins with altered binding affinity for the macromolecule.
Claims20
1-89. (canceled)
A method for calculating the Spatial-Aggregation-Propensity (SAP) for a particular atom in a protein, comprising
- (i) identifying one or more atoms or amino acid residues in a structural model representing the protein, wherein the one or more atoms are within a defined spatial region centered on or near the particular atom or the one or more amino acid residues have at least one atom within a defined spatial region centered on or near the particular atom;
- (ii) calculating, for the one or more atoms in the defined spatial region, a ratio of the solvent accessible area (SAA) of the atoms to the SAA of atoms in an identical residue which is fully exposed;
- (iii) multiplying each ratio by the atom hydrophobicity of the one or more atoms;
- and
- (iv) summing the products of step (c);
- whereby the sum is the SAP for the particular atom;
- and
- wherein, optionally, the SAP for the particular atom is calculated by conducting a molecular dynamics simulation prior to step (i) and repeating steps (i)-(iv), each time conducting a further molecular dynamics simulation at a plurality of time steps, thereby producing multiple sums as in step (iv), and calculating the average of the sums;
- whereby the calculated average is the SAP for the particular atom
Dependencies are inferred from the claim text.