Editing ChargeCalculator:Case studies (section)

=Protegrin-1 – atomic charges and activity of antimicrobial peptides=

[[File:Protegrin.png|thumb|right|300px| Residue centroids represented by spheres colored by residue charges. Residues ARG4 and ARG9 are significantly less positive (lighter blue) than the rest of the ARG residues (darker blue), indicating that mutations at these positions may be less effective.]]

Protegrins are a family of antimicrobial peptides active against a wide range of pathogens. Protegrin-1 (PG1) has been intensely studied for its potential in treating infections caused by antibiotic resistant bacteria. PG1 shows activity against several pathogens, but also toxicity against the host. Useful mutations are those which maintain the antimicrobial activity, and at the same time reduce toxicity.

We calculated atomic charges in PG1 using ACC. The geometry of the PG1 molecule corresponded to the lowest energy NMR model in the entry 1PG1 (PDB: 1PG1) from the Protein Data Bank. The computation took less than 1s, and the complete results are available on the [http://ncbr.muni.cz/ACC/CaseStudy/Protegrin ACC web page].

The calculation produced one set of atomic charges. PG1 contains 18 residues, and rather than analyzing atomic charges, we analyzed the residue charges, which are also reported by ACC (Figure 4B). PG1 is special because of its high positive charge. It contains 6 ARG residues. However, not all have the same charge. In particular, ARG at positions 4 and 9 have the least positive charge (around +0.5e), whereas the rest have much higher positive charge (over +0.8e). Such results suggest that mutations of ARG into a neutral residue at positions 4 or 9 would have a lower effect than mutations at positions 1, 10, 11 or 18. This seems to be indeed the case, as it was found that the mutation of ARG 4 alters the antimicrobial activity against C. albicans significantly less than the mutation of ARG 10. Such biologically relevant insight can be gained by analyzing the residue charges on a single structure of PG1.
 
You can try out this particular computation setup [http://webchem.ncbr.muni.cz/Platform/ChargeCalculator/Result/dc41612f-b3c0-4207-97a6-b70598e90d88?example=Protegrin here], and make sure to use the interactive guides for additional explanations. The total molecular charge was +7, owing to the many ARG residues. The EEM parameter set used was EX-NPA_6-31Gd_gas, but it was necessary to add to this set EEM parameters for deuterium (D), because this element was present in the input file. The EEM parameters for D were identical to the parameters for H. The EEM parameter set covers NPA atomic charges at the HF/6-31G* level of theory. These charges are expected to support qualitative chemical concepts like induction and conjugation. The rest of the ACC default settings were kept.
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