Journal article Open Access

Benchmarking a Fast Proton Titration Scheme in Implicit Solvent for Biomolecular Simulations

Fernando Luís Barroso da Silva; Donal MacKernan

pH is a key parameter for technological and biological processes, intimately related
to biomolecular charge. As such, it controls biomolecular conformation and inter
molecular interactions, for example, protein/RNA stability and folding, enzyme activity,
regulation through conformational switches,protein-polyelectrolyte association,
and protein-RNA interactions. pH also plays an important role in technological systems
in food, brewing, pharma, bioseparations and biomaterials in general. Predicting the structure of large proteins and complexes remains a great challenge, experimentally,
industrially, and theoretically, despite the variety of numerical schemes available
ranging from Poisson-Boltzmann approaches to explicit solvent based methods. In this
work we benchmark a fast proton titration scheme against experiment and several theoretical
methods on the following set of representative proteins: [HP36, BBL, HEWL
(triclinic and orthorhombic), RNase, SNASE (V66K/WT, V66K/PHS, V66K/+PHS,
L38D/+PHS, L38E/+PHS, L38K/+PHS), ALAC and OMTKY3] routinely used
in similar tests due to the diversity of their structural features. Our scheme is rooted in
the classical Tanford-Kirkwood model of impenetrable spheres, where salt is treated at
the Debye-Hückel level. Treating salt implicitly dramatically reduces the computation
time, thereby circumventing sampling difficulties faced by other numerical schemes.
In comparison with experimental measurements, our calculated pKa values have the
average, maximum absolute and root-mean-square deviations of [0.4 − 0.9], [1.0 − 5.2]
and [0.5 − 1.2] pH units, respectively. These values are within the ranges commonly
observed in theoretical models. They are also in the large majority of the cases studied
here more accurate than the NULL model. For BBL, ALAC and OMTKY3, the
predicted pKa are closer to experimental results than other analyzed theoretical data.
Despite the intrinsic approximations of the fast titration scheme, its robustness and
ability to properly describe the main system physics is confirmed.

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