Dataset Information

PKa determination of histidine residues in ?-conotoxin MII peptides by 1H NMR and constant pH molecular dynamics simulation.

ABSTRACT: ?-Conotoxin MII (?-CTxMII) is a potent and selective peptide antagonist of neuronal nicotinic acetylcholine receptors (nAChR's). Studies have shown that His9 and His12 are significant determinants of toxin binding affinity for nAChR, while Glu11 may dictate differential toxin affinity between nAChR isoforms. The protonation state of these histidine residues and therefore the charge on the ?-CTx may contribute to the observed differences in binding affinity and selectivity. In this study, we assess the pH dependence of the protonation state of His9 and His12 by (1)H NMR spectroscopy and constant pH molecular dynamics (CpHMD) in ?-CTxMII, ?-CTxMII[E11A], and the triple mutant, ?-CTxMII[N5R:E11A:H12K]. The E11A mutation does not significantly perturb the pKa of His9 or His12, while N5R:E11A:H12K results in a significant decrease in the pKa value of His9. The pKa values predicted by CpHMD simulations are in good agreement with (1)H NMR spectroscopy, with a mean absolute deviation from experiment of 0.3 pKa units. These results support the use of CpHMD as an efficient and inexpensive predictive tool to determine pKa values and structural features of small peptides critical to their function.

SUBMITTER: McDougal OM

PROVIDER: S-EPMC3632324 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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pKa determination of histidine residues in α-conotoxin MII peptides by 1H NMR and constant pH molecular dynamics simulation.

McDougal Owen M OM Granum David M DM Swartz Mark M Rohleder Conrad C Maupin C Mark CM

The journal of physical chemistry. B 20130225 9

α-Conotoxin MII (α-CTxMII) is a potent and selective peptide antagonist of neuronal nicotinic acetylcholine receptors (nAChR's). Studies have shown that His9 and His12 are significant determinants of toxin binding affinity for nAChR, while Glu11 may dictate differential toxin affinity between nAChR isoforms. The protonation state of these histidine residues and therefore the charge on the α-CTx may contribute to the observed differences in binding affinity and selectivity. In this study, we asse ...[more]

PMID: 23336579

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Project description:We present a GPU implementation of the continuous constant pH molecular dynamics (CpHMD) based on the most recent generalized Born implicit-solvent model in the pmemd engine of the Amber molecular dynamics package. To test the accuracy of the tool for rapid pKa predictions, a series of 2 ns single-pH simulations were performed for over 120 titratable residues in 10 benchmark proteins that were previously used to test the various continuous CpHMD methods. The calculated pKa's showed a root-mean-square deviation of 0.80 and correlation coefficient of 0.83 with respect to experiment. Also, 90% of the pKa's were converged with estimated errors below 0.1 pH units. Surprisingly, this level of accuracy is similar to our previous replica-exchange simulations with 2 ns per replica and an exchange attempt frequency of 2 ps-1 (Huang, Harris, and Shen J. Chem. Inf. Model. 2018 , 58 , 1372 - 1383 ). Interestingly, for the linked titration sites in two enzymes, although residue-specific protonation state sampling in the single-pH simulations was not converged within 2 ns, the protonation fraction of the linked residues appeared to be largely converged, and the experimental macroscopic pKa values were reproduced to within 1 pH unit. Comparison with replica-exchange simulations with different exchange attempt frequencies showed that the splitting between the two macroscopic pKa's is underestimated with frequent exchange attempts such as 2 ps-1, while single-pH simulations overestimate the splitting. The same trend is seen for the single-pH vs replica-exchange simulations of a hydrogen-bonded aspartyl dyad in a much larger protein. A 2 ns single-pH simulation of a 400-residue protein takes about 1 h on a single NVIDIA GeForce RTX 2080 graphics card, which is over 1000 times faster than a CpHMD run on a single CPU core of a high-performance computing cluster node. Thus, we envision that GPU-accelerated continuous CpHMD may be used in routine pKa predictions for a variety of applications, from assisting MD simulations with protonation state assignment to offering pH-dependent corrections of binding free energies and identifying reactive hot spots for covalent drug design.

Dataset Information

PKa determination of histidine residues in ?-conotoxin MII peptides by 1H NMR and constant pH molecular dynamics simulation.

Publications

pKa determination of histidine residues in α-conotoxin MII peptides by 1H NMR and constant pH molecular dynamics simulation.

Similar Datasets

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