Methods For Determining Correlated Residues In A Protein Or Other Biopolymer Using Molecular Dynamics

摘要

The invention provides methods and systems of determining biopolymer profiles and correlations between structural units (residues) of a biopolymer based on sampling of the conformational space available to the molecule. The correlations between these structural units can further be used to find networks within a biopolymer such as the coupled residue networks in a protein. The invention also provides for designing and engineering biopolymers including polypeptides, nucleic acids and carbohydrates using the information derived from the conformation clustering and subsequent methods described herein.

主权项

1. A method of engineering a variant of a biopolymer, wherein the biopolymer comprises a plurality of component structural units, the method comprising:
a) performing a simulation to calculate at least one trajectory for a plurality of geometric metrics using a three-dimensional atomic model of the biopolymer, wherein
the plurality of geometric metrics comprises a intra-component structural unit plane metric or an intra-component structural unit dihedral angle metric or an intra-component structural unit distance metric for each individual component structural unit in the plurality of component structural units; b) determining at least one structural unit conformation for each corresponding component structural unit in the plurality of component structural units, wherein
the at least one structural unit conformation of a corresponding component structural unit in the plurality of component structural units is obtained by clustering first conformation information for the corresponding component structural unit in the at least one trajectory, wherein the first conformation information comprises a subset of geometric metrics or the plurality of geometric metrics for the corresponding component structural unit; c) determining a conformational frequency of each the at least one structural unit conformation of each component structural unit in the plurality of component structural units; d) determining a variance in the first conformation information of each the at least one structural unit conformation of each component structural unit in the plurality of component structural units; and e) assigning a mobility index to each respective component structural unit in the plurality of component structural units based on the corresponding conformational frequency and the variance in the first conformation information of each structural unit conformation in the at least one structural unit conformation of the respective component structural unit; and f) making the variant of the biopolymer, wherein the variant of the biopolymer comprises the sequence of the biopolymer in which a first component structural unit of the biopolymer has been substituted in the variant of the biopolymer for a different component structural unit at least partly on the basis of the mobility index for the component structural unit.