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. 2010 Feb 9;6(2):560-568.
doi: 10.1021/ct9005294. Epub 2010 Jan 14.

Coupling Constant pH Molecular Dynamics with Accelerated Molecular Dynamics

Sarah L Williams  1 , César Augusto F de Oliveira, J Andrew McCammon
Affiliations

Coupling Constant pH Molecular Dynamics with Accelerated Molecular Dynamics

Sarah L Williams et al. J Chem Theory Comput. .

Abstract

An extension of the constant pH method originally implemented by Mongan et al. (J. Comput. Chem.2004, 25, 2038-2048) is proposed in this study. This adapted version of the method couples the constant pH methodology with the enhanced sampling technique of accelerated molecular dynamics, in an attempt to overcome the sampling issues encountered with current standard constant pH molecular dynamics methods. Although good results were reported by Mongan et al. on application of the standard method to the hen egg-white lysozyme (HEWL) system, residues which possess strong interactions with neighboring groups tend to converge slowly, resulting in the reported inconsistencies for predicted pK(a) values, as highlighted by the authors. The application of the coupled method described in this study to the HEWL system displays improvements over the standard version of the method, with the improved sampling leading to faster convergence and producing pK(a) values in closer agreement to those obtained experimentally for the more slowly converging residues.

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Figures

Figure 1
Figure 1
The HEWL enzyme (PDB ID: 1AKI) with titratable groups highlighted in liquorice style (aspartates, blue; glutamates, red; and histidine, orange).
Figure 2
Figure 2
The RMSD of CA atoms with respect to the crystal structure, over the duration of 5 ns simulations carried out at pH 2.0, 4.0, and 6.0 using CPH-aMD (lower plot) and CpHMD (upper plot).
Figure 3
Figure 3
pKa values of titratable residues over the duration of 5 ns simulations employing CpHMD (top two plots) and CpHaMD (lower two plots) at pH 3.0 (plots a and c) and pH 6.5 (plots b and d).
Figure 4
Figure 4
pKa values of titratable residues over the duration of 40 ns CPMD (top two plots) and CpHaMD (lower two plots) simulations at pH 3.0 (plots a, c) and pH 6.5 (plots b, d).
Figure 5
Figure 5
Conformational sampling of residues (502 atoms) within 7.5 Å of ASP-52 demonstrated by PCA analysis. Eigenvectors generated from the concatenation of trajectories of simulations carried out at pH 6.5. Red: sampling from simulation carried out using CpHaMD. Black: sampling from simulation carried out using CpHMD.
Figure 6
Figure 6
Motion of loop allowing the dissociation of the ASP-52−ASN-46 interaction in simulations employing CpHaMD methodology.
Figure 7
Figure 7
Transitions between protonated (1) and deprotonated (0) states of ASP-52 over a 40 ns CpHaMD simulation at pH 6.5.
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References

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