Computing Thermodynamic Effects of Atomic Polymer Changes
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing methods fail to accurately quantify the thermodynamic effects of atomic changes in proteins due to size differences between mutant and wild-type residues, making it difficult to assess changes in conformational flexibility.
Innovation Solution
A method that computes local thermodynamic differences between native and mutated proteins by using structurally refined three-dimensional coordinates and atomistic Hessians to isolate the effects of atomic replacements, insertions, or deletions, allowing for the calculation of conformational flexibility changes in specific protein regions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If total molecular entropy is used to quantify conformational flexibility, then the measure is thermodynamically natural, but the comparison between polymers of different primary sequence becomes uninformative due to different numbers of degrees of freedom
Solution Approach 1:
The patent divides the polymer into segments: the mutated residue and the environment about the residue. By calculating entropy contributions separately for these segments and comparing only the environment portion, the method enables meaningful comparisons across different polymers while maintaining thermodynamic rigor.
Solution Approach 2:
The patent focuses on local conformational flexibility in the environment about the mutation site rather than global molecular entropy. This local approach allows for meaningful comparisons between different polymers by examining specific regions with consistent degrees of freedom.
2Measurement precision
If total molecular entropy is calculated for mutated and native proteins, then thermodynamic quantification is achieved, but the size difference between mutant and wild type residues masks the true conformational freedom changes
Solution Approach 1:
The patent extracts the entropy contribution of the mutated residue from the total molecular entropy to isolate the entropy contribution of the environment. This extraction reveals the true conformational freedom changes in the environment that were previously masked by the size difference between mutant and wild type residues.
Solution Approach 2:
The patent calculates the full entropy but then selectively uses only the environmental portion for comparison purposes. This partial use of the calculated entropy allows for accurate assessment of conformational freedom changes without the confounding effects of residue size differences.
3Ease of manufacture
If conventional entropy calculations are used, then computational simplicity is maintained, but the ability to assess local conformational flexibility changes is lost
Solution Approach 1:
The patent segments the entropy calculation into residue-specific and environmental components. This segmentation enables local conformational flexibility assessment while maintaining computational feasibility by reusing existing entropy calculation methodologies applied to different spatial regions.
Solution Approach 2:
The patent introduces an environmental region as an intermediary between the mutation site and the rest of the polymer. This intermediary region serves as the basis for assessing local conformational flexibility changes while maintaining a clear computational framework that builds upon conventional entropy calculations.
Data Source
Figure 1
Figure 2
Figure 3
AI summary
Systems and methods for evaluating thermodynamics of atomic changes in a polymer include using a first portion of a refined derived set of three-dimensional coordinates for a derivation of the polymer, which incorporates the atomic change under study, to compute a first effective atomistic Hessian. A second effective atomistic Hessian is computed using a second portion of a refined native set of three- dimensional coordinates for the native polymer. Atoms in the first and second portions are identical. A thermodynamic property of the first portion is determined using the refined derived set of three-dimensional coordinates and the first effective atomistic Hessian. A thermodynamic property of the second portion of the native polymer is determined using the refined native set of three-dimensional coordinates and the second effective atomistic Hessian. The effect of the atomic changes is quantified by taking the difference between the calculated thermodynamic properties of the first and second portions.