A comparison of different initialization protocols to obtain statistically independent molecular dynamics simulations

Abstract

We study how the results of molecular dynamics (MD) simulations are affected by various choices during the setup, e.g., the starting velocities, the solvation, the location of protons, the conformation of His, Asn, and Gln residues, the protonation and titration of His residues, and the treatment of alternative conformations. We estimate the binding affinity of ligands to four proteins calculated with the MM/GBSA method (molecular mechanics combined with a generalized Born and surface area solvation energy). For avidin and T4 lysozyme, all variations gave similar results within 2 kJ/mol. For factor Xa, differences in the solvation or in the selection of alternative conformations gave results that are significantly different from those of the other approaches by 4–6 kJ/mol, whereas for galectin‐3, changes in the conformations, rotations, and protonation gave results that differed by 10 kJ/mol, but only if residues close to the binding site were modified. This shows that the results of MM/GBSA calculations are reasonably reproducible even if the MD simulations are set up with different software. Moreover, we show that the sampling of phase space can be enhanced by solvating the systems with different equilibrated water boxes, in addition to the common use of different starting velocities. If different conformations are available in the crystal structure, they should also be employed to enhance the sampling. Protonation, ionization, and conformations of Asn, Gln, and His may also be used to enhance sampling, but great effort should be spent to obtain as reliable predictions as possible close to the active site. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2011

Can the protonation state of histidine residues be determined from molecular dynamics simulations?

“…On the other hand, this is a very important conclusion, showing that the problematic and often quite arbitrary choice of the protonation state of the His residues has a minor influence of the structure of the protein when the hydrogen-bond analysis does not give any conclusive results. This is also in accordance with the observation that ligandbinding free energies are insensitive to the protonation of His residues in the protein, except when they are in direct contact with the ligand [27]. Consequently, that the analysis of the His protonation may be concentrated around a possible site of central interest.…”

Will molecular dynamics simulations of proteins ever reach equilibrium?

“…38,72,73,74,75,76,77 Therefore, we also calculated the entropy from ten independent simulations of 10 (MMP12) or 20 ns (Gal3) length. The average entropies over these simulations are shown in Table 1 together with the corresponding standard errors (i.e.…”

Free-energy perturbation and quantum mechanical study of SAMPL4 octa-acid host–guest binding energies

“…The cut-off for non-bonded interactions was set to 10 Å. For the Bz and EtBz guests (the names of the guests are specified in Figure 1), ten independent simulations were performed by rotating the complex by a random angle around a random axis before the solvation and employing different starting velocities (the rotations were performed to ensure that the complexes were solvated differently, increasing the difference between the independent simulations [35]). …”