Mapping hydrophobicity on the protein molecular surface at atom-level resolution.

Dan V Nicolau Jr,Florin Fulga,Ewa Paszek,Dan V Nicolau

doi:10.1371/journal.pone.0114042

Abstract

A precise representation of the spatial distribution of hydrophobicity, hydrophilicity and charges on the molecular surface of proteins is critical for the understanding of the interaction with small molecules and larger systems. The representation of hydrophobicity is rarely done at atom-level, as this property is generally assigned to residues. A new methodology for the derivation of atomic hydrophobicity from any amino acid-based hydrophobicity scale was used to derive 8 sets of atomic hydrophobicities, one of which was used to generate the molecular surfaces for 35 proteins with convex structures, 5 of which, i.e., lysozyme, ribonuclease, hemoglobin, albumin and IgG, have been analyzed in more detail. Sets of the molecular surfaces of the model proteins have been constructed using spherical probes with increasingly large radii, from 1.4 to 20 Å, followed by the quantification of (i) the surface hydrophobicity; (ii) their respective molecular surface areas, i.e., total, hydrophilic and hydrophobic area; and (iii) their relative densities, i.e., divided by the total molecular area; or specific densities, i.e., divided by property-specific area. Compared with the amino acid-based formalism, the atom-level description reveals molecular surfaces which (i) present an approximately two times more hydrophilic areas; with (ii) less extended, but between 2 to 5 times more intense hydrophilic patches; and (iii) 3 to 20 times more extended hydrophobic areas. The hydrophobic areas are also approximately 2 times more hydrophobicity-intense. This, more pronounced “leopard skin”-like, design of the protein molecular surface has been confirmed by comparing the results for a restricted set of homologous proteins, i.e., hemoglobins diverging by only one residue (Trp37). These results suggest that the representation of hydrophobicity on the protein molecular surfaces at atom-level resolution, coupled with the probing of the molecular surface at different geometric resolutions, can capture processes that are otherwise obscured to the amino acid-based formalism.

Highlights

The shape of, and the physico-chemical properties on the protein molecular surfaces govern the specific molecular interactions in protein-ligand complexes [1]
The present study proposes a methodology for the derivation of atomic hydrophobicity from any hydrophobicity scale, runs a sensitivity analysis to assess the suitability of alternative atom types, and compares the results obtained with atom- and amino acid-level representation of hydrophobicity on molecular surfaces
As the hydrophobicity is usually assigned to amino acids not to atoms, its spatial representation on the protein molecular surface is constructed at several-atoms resolution, i.e., from patches comprising several atoms belonging to a parent amino acid, which is probed by the molecular surface probing ball

Summary

Introduction

The shape of, and the physico-chemical properties on the protein molecular surfaces govern the specific molecular interactions in protein-ligand complexes [1]. Studies as diverse as those on protein folding [2], protein conformational stability [3], inter- and intra- protein interactions [4], molecular recognition [5] and docking [6]; as well as applications-orientated ones, such as drug design [7, 8], protein and peptide solubility [9], crystal packing [10], and enzyme catalysis [11], benefit from an accurate and precise representation of the molecular surfaces. Because the biomolecular recognition is a geometrically-localized and charge- and hydrophobicity-specific event, its accurate description requires the representation of molecular surfaces with the finest resolution possible. Several studies [15,16,17,18,19,20] developed ‘‘atomic hydrophobicities’’ proposing different sets of atom types, but a sensitivity analysis regarding the number of atom types, as well as study comparing the protein molecular surfaces obtained using atom- or amino acid-level hydrophobicity is lacking

Methods

Results

Conclusion