# Three-Dimensional Interaction Homology: Deconstructing Residue–Residue and Residue–Lipid Interactions in Membrane Proteins

## TL;DR

This paper introduces a method to map interactions between protein residues and their environment, including lipids, in three dimensions to better understand membrane protein structures.

## Contribution

The novel contribution is a backbone angle-dependent method to deconstruct residue–environment interactions into 3D maps, particularly for lipid-facing transmembrane domains.

## Key findings

- Residue-based 3D interaction maps reveal optimal positions and strengths of hydrophobic and polar interactions.
- Lipid-facing transmembrane residues provide detailed protein–lipid interaction maps that are experimentally hard to obtain.
- The number of unique interaction maps per residue depends on its size and interaction complexity.

## Abstract

A method is described to deconstruct the network of hydropathic interactions within and between a protein’s sidechain and its environment into residue-based three-dimensional maps. These maps encode favorable and unfavorable hydrophobic and polar interactions, in terms of spatial positions for optimal interactions, relative interaction strength, as well as character. In addition, these maps are backbone angle-dependent. After map calculation and clustering, a finite number of unique residue sidechain interaction maps exist for each backbone conformation, with the number related to the residue’s size and interaction complexity. Structures for soluble proteins (~749,000 residues) and membrane proteins (~387,000 residues) were analyzed, with the latter group being subdivided into three subsets related to the residue’s position in the membrane protein: soluble domain, core-facing transmembrane domain, and lipid-facing transmembrane domain. This work suggests that maps representing residue types and their backbone conformation can be reassembled to optimize the medium-to-high resolution details of a protein structure. In particular, the information encoded in maps constructed from the lipid-facing transmembrane residues appears to paint a clear picture of the protein–lipid interactions that are difficult to obtain experimentally.