Project pHinder

This project explores structure-based relationships using computational geometry.

Source code: github.com/isomlab/pHinder. pHinder is a self-contained, installable Python package (phinder CLI and phinder-gui GUI) — it needs no other lab repository. See the repository README for installation; conda packaging is in progress.

• code — the version used in the associated manuscript, kept for archival completeness
• example_input

🧬 What pHinder Does

pHinder is a computational toolkit for analyzing the 3D structure of proteins, with a focus on side chain topology and burial. Originally developed to identify buried ionizable networks, pHinder has evolved into a general-purpose platform for side chain classification and surface-based structural analysis.

🔍 Key Capabilities

• Topological Classification of Side Chains
  Assigns each side chain as core, margin, or exposed based on its spatial relationship to a calculated molecular surface.

• Molecular Surface Construction
  Builds and refines a triangulated surface around the protein using Cα-based Delaunay triangulation, enabling depth-based residue analysis.

• Network Detection and Scoring
  Identifies contiguous networks of side chains (especially ionizable ones) based on proximity and burial, useful for exploring electrostatic or functional microenvironments.

• Flexible Residue Sets
  Supports predefined or custom residue sets, including ionizable, acidic, basic, polar, apolar, or user-defined residues.

• Burial-Based Filtering for Functional Inference
  Useful for inferring sites of potential structural stabilization, altered pKa behavior, or ligand interaction hotspots.

• Generalization Beyond Electrostatics
  While originally tailored to ionizable side chains, pHinder now supports broad structural analysis of any side chain class, making it a versatile tool in protein structural biology.

🛠️ Additional Functionalities

• Protein-Protein Interface Detection
  Automatically identifies interaction surfaces between two or more protein chains, facilitating the study of multimeric assemblies and complex formation.

• Ligand and Drug Binding Site Identification
  Predicts buried and surface-accessible cavities that may serve as potential ligand or drug binding sites, supporting virtual screening workflows.

📚 Citations

If you use pHinder in your work, please cite the following publications that describe the method and its applications:

1. Isom DG, Sridharan V, Baker R, Clement ST, Smalley DM, Dohlman HG. Protons as second messenger regulators of G protein signaling. Mol Cell. 2013 Aug 22;51(4):531-8. doi: 10.1016/j.molcel.2013.07.012. PMID: 23954348
2. Isom DG, Dohlman HG. Buried ionizable networks are an ancient hallmark of G protein-coupled receptor activation. Proc Natl Acad Sci U S A. 2015 May 5;112(18):5702-7. doi: 10.1073/pnas.1417888112. PMID: 25902551
3. Isom DG, Sridharan V, Dohlman HG. Regulation of Ras Paralog Thermostability by Networks of Buried Ionizable Groups. Biochemistry. 2016 Jan 26;55(3):534-42. doi: 10.1021/acs.biochem.5b00901. PMID: 26701741
4. Isom DG, Page SC, Collins LB, Kapolka NJ, Taghon GJ, Dohlman HG. Coordinated regulation of intracellular pH by two glucose-sensing pathways in yeast. J Biol Chem. 2018 Feb 16;293(7):2318-2329. doi: 10.1074/jbc.RA117.000422. PMID: 29284676
5. Luna LA, Lesecq Z, White KA, Hoang A, Scott DA, Zagnitko O, Bobkov AA, Barber DL, Schiffer JM, Isom DG, Sohl CD. An acidic residue buried in the dimer interface of isocitrate dehydrogenase 1 (IDH1) helps regulate catalysis and pH sensitivity. Biochem J. 2020 Aug 28;477(16):2999-3018. doi: 10.1042/BCJ20200311. PMID: 32729927
6. Rowe JB, Kapolka NJ, Taghon GJ, Morgan WM, Isom DG. The evolution and mechanism of GPCR proton sensing. J Biol Chem. 2021 Jan-Jun;296:100167. doi: 10.1074/jbc.RA120.016352. PMID: 33478938
7. Taghon GJ, Rowe JB, Kapolka NJ, Isom DG. Predictable cholesterol binding sites in GPCRs lack consensus motifs. Structure. 2021 May 6;29(5):499-506.e3. doi: 10.1016/j.str.2021.01.004. PMID: 33508215