Dataset Information

Electrostatic Similarity Analysis of Human ?-Defensin Binding in the Melanocortin System.

ABSTRACT: The ?-defensins are a class of small cationic proteins that serve as components of numerous systems in vertebrate biology, including the immune and melanocortin systems. Human ?-defensin 3 (HBD3), which is produced in the skin, has been found to bind to melanocortin receptors 1 and 4 through complementary electrostatics, a unique mechanism of ligand-receptor interaction. This finding indicates that electrostatics alone, and not specific amino acid contact points, could be sufficient for function in this ligand-receptor system, and further suggests that other small peptide ligands could interact with these receptors in a similar fashion. Here, we conducted molecular-similarity analyses and functional studies of additional members of the human ?-defensin family, examining their potential as ligands of melanocortin-1 receptor, through selection based on their electrostatic similarity to HBD3. Using Poisson-Boltzmann electrostatic calculations and molecular-similarity analysis, we identified members of the human ?-defensin family that are both similar and dissimilar to HBD3 in terms of electrostatic potential. Synthesis and functional testing of a subset of these ?-defensins showed that peptides with an HBD3-like electrostatic character bound to melanocortin receptors with high affinity, whereas those that were anticorrelated to HBD3 showed no binding affinity. These findings expand on the central role of electrostatics in the control of this ligand-receptor system and further demonstrate the utility of employing molecular-similarity analysis. Additionally, we identified several new potential ligands of melanocortin-1 receptor, which may have implications for our understanding of the role defensins play in melanocortin physiology.

SUBMITTER: Nix MA

PROVIDER: S-EPMC4643202 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Electrostatic Similarity Analysis of Human β-Defensin Binding in the Melanocortin System.

Nix Matthew A MA Kaelin Christopher B CB Palomino Rafael R Miller Jillian L JL Barsh Gregory S GS Millhauser Glenn L GL

Biophysical journal 20151101 9

The β-defensins are a class of small cationic proteins that serve as components of numerous systems in vertebrate biology, including the immune and melanocortin systems. Human β-defensin 3 (HBD3), which is produced in the skin, has been found to bind to melanocortin receptors 1 and 4 through complementary electrostatics, a unique mechanism of ligand-receptor interaction. This finding indicates that electrostatics alone, and not specific amino acid contact points, could be sufficient for function ...[more]

PMID: 26536271

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Project description:We introduce a new method for rapid computation of 3D molecular similarity that combines electrostatic field comparison with comparison of molecular surface-shape and directional hydrogen-bonding preferences (called "eSim"). Rather than employing heuristic "colors" or user-defined molecular feature types to represent conformation-dependent molecular electrostatics, eSim calculates the similarity of the electrostatic fields of two molecules (in addition to shape and hydrogen-bonding). We present detailed virtual screening performance data on the standard 102 target DUD-E set. In its moderately fast screening mode, eSim running on a single computing core is capable of processing over 60 molecules per second. In this mode, eSim performed significantly better than all alternate methods for which full DUD-E data were available (mean ROC area of 0.74, p [Formula: see text], by paired t-test, compared with the best performing alternate method). In addition, for 92 targets of the DUD-E set where multiple ligand-bound crystal structures were available, screening performance was assessed using alternate ligands or sets thereof (in their bound poses) as similarity targets. Using the joint alignment of five ligands for each protein target, mean ROC area exceeded 0.82 for the 92 targets. Design-focused application of ligand similarity methods depends on accurate predictions of geometric molecular relationships. We comprehensively assessed pose prediction accuracy by curating nearly 400,000 bound ligand pose pairs across the DUD-E targets. Overall, beginning from agnostic initial poses, we observed an 80% success rate for RMSD [Formula: see text] Å among the top 20 predicted eSim poses. These examples were split roughly 50/50 into cases with high direct atomic overlap (where a shared scaffold exists between a pair) and low direct atomic overlap (where where a ligand pair has dissimilar scaffolds but largely occupies the same space). Within the high direct atomic overlap subset, the pose prediction success rate was 93%. For the more challenging subset (where dissimilar scaffolds are to be aligned), the success rate was 70%. The eSim approach enables both large-scale screening and rational design of ligands and is rooted in physically meaningful, non-heuristic, molecular comparisons.

Dataset Information

Electrostatic Similarity Analysis of Human ?-Defensin Binding in the Melanocortin System.

Publications

Electrostatic Similarity Analysis of Human β-Defensin Binding in the Melanocortin System.

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