Dimerization of Protegrin-1 in Different Environments
Abstract
:1. Introduction
2. Methods
2.1. Microscopic Models for PG1 Dimers in the Water Phase, on the Surface of a POPG:POPE Membrane and inside a POPG:POPE Membrane
Environment 1: Water Subphase
Environment 2: Lipid Bilayer Surface
Environment 3: Lipid Bilayer Core
2.2. Molecular Dynamics Protocol
2.3. Construction of Potential of Mean Force (PMF) for the Formation of PG1pd and PG1ad
- The two peptides are positioned in either the parallel or antiparallel orientation, at a distance D. The peptide separation, D, ranges from 9 Å to 25 Å in increments of 2 Å. There are thus 54 systems constructed (two orientations, three environments, nine separation distances). We should note that for PG1pd in Environment 3, we added another separation distance of D = 27 Å, in order to ascertain that the PMF attains a plateau at long distances, as discussed in more detail in Section 3. Each of the 55 constructed system is then equilibrated over 4 ns in the NPT ensemble. During this equilibration the PG1 peptides are restrained using harmonic springs with a a force constant 20 (kcal/mol)/Å2 applied to all peptide backbone atoms.
- A 4 ns production run is then conducted for each of the 55 initial equilibrated systems. In production runs, and in order to restrain the peptides and their orientations, we use harmonic springs coupled to the three carbon CB backbone atoms of Arg1, Arg10 and Cys15. All spring constants were 20 (kcal/mol)/Å2. In addition, and in order to better ascertain convergence of the PMF calculation, we extended the simulation of the parallel configuration, PG1pd, inside the membrane by an additional 4 ns, to 8 ns, for all examined distances.
- The instantaneous restraint forces are computed for each of the 55 system configurations for PG1 dimers with a sampling interval of 0.2 ps, and averaged to obtain the mean force F̄ (D) = −F̄res (D) for each position, where F̄res (D) is the force exerted on the harmonic restraint springs. We concentrate our efforts on reducing the statistical errors. A difficulty is that, on short time scales, the results are highly correlated, and thus unsuitable for statistical analysis. We find that the correlation time for estimating the error due to solvent force fluctuations is about 0.1 ns, and membrane fluctuations and systematic error due to the harmonic restraints require data for no less than 0.5 ns to compute reliable average forces. Using the block-averaging method [27] we find the statistical errors in F̄res (D) to be within 0.4 (kcal/mol)/Å in all cases. The total sampling time must therefore be long enough to ensure a collection of uncorrelated configurations.
- The PMF can be evaluated by applying the mean force integration method which was developed for the PMF calculation of a peptide in the vicinity of a neutral POPC membrane [28]. This method is a variant of constrained MD and thermodynamic integration [29–34]. In particular, the PMF, W(D), is calculated using (1), where the integration over the D coordinate is performed using the trapezoidal rule:
3. Results and Discussion
3.1. Binding Affinity of PG1 Peptides in the Parallel and Antiparallel β-Sheet Arrangements
3.2. The Role of Ionic Bridge and Hydrogen Bond Networks in Dimerization Stability
Ionic Bridges
Hydrogen bonds
4. Conclusions
Acknowledgements
- Classification: PACS 87.15.-v
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Vivcharuk, V.; Kaznessis, Y.N. Dimerization of Protegrin-1 in Different Environments. Int. J. Mol. Sci. 2010, 11, 3177-3194. https://doi.org/10.3390/ijms11093177
Vivcharuk V, Kaznessis YN. Dimerization of Protegrin-1 in Different Environments. International Journal of Molecular Sciences. 2010; 11(9):3177-3194. https://doi.org/10.3390/ijms11093177
Chicago/Turabian StyleVivcharuk, Victor, and Yiannis N. Kaznessis. 2010. "Dimerization of Protegrin-1 in Different Environments" International Journal of Molecular Sciences 11, no. 9: 3177-3194. https://doi.org/10.3390/ijms11093177