OPEP6: A New Constant-pH Molecular Dynamics Simulation Scheme with OPEP Coarse-Grained Force Field.

The great importance of pH for molecular processes has motivated the continuous development of numerical methods to improve the physical description of molecular mechanisms in computer simulations. Although rigid titration models are able to provide several pieces of useful information, the coupling between the molecular conformational changes and the acid-base equilibrium is necessary to more completely model the pH effects in biomolecules. Previously reported convergence issues with atomistic simulations indicated that a promising approach would require coarse-grained models. By means of the coupling between the successful OPEP force field for proteins with the fast proton titration scheme, we proposed a new protocol for constant-pH molecular dynamics simulations that takes advantage of both coarse-grained approaches to circumvent sampling difficulties faced by other numerical schemes and also to be able to properly describe electrostatic and structural properties at lower CPU costs. Here, we introduce this new protocol that defines now OPEP6 and its p Ka's benchmark for a set of representative proteins (HP36, BBL, HEWL, NTL9, and a protein G variant). In comparison with experimental measurements, our calculated p Ka values have the average, maximum absolute, and root-mean-square deviations of [0.3-1.1], [0.6-2.5], and [0.4-1.3] pH units, respectively, for these five studied proteins. These numbers are within the ones commonly observed when similar comparisons are done among different theoretical models and are slightly better than the accuracy obtained by a rigid model using the same titration engine. For BBL, the predicted p Ka are closer to experimental results than other analyzed theoretical data. Structural properties were tested for insulin where separation distances between the groups were compared and found in agreement with experimental crystallographic data obtained at different pH conditions. These indicate the ability of the new OPEP to properly describe the system physics and open up more possibilities to study pH-mediated biological processes.