The study of biologically relevant macromolecules at the molecular level has been challenging for quite some time for researchers. In recent years, molecular modeling and simulation is the field of research that probably has more enthusiastically contributed with atomistic information.
In computational studies, the pH effects on biologically relevant molecules have been addressed with several limitations. Biological membranes are inherently complex and some important aspects, like protonation equilibrium, have also been unsatisfactorily modeled. The complexity of the membrane/water interface in biological membranes can even increase many-fold due to the presence of a myriad of different lipid molecules in their composition (e.g. anionic lipids). The convoluted contribution of the complex electrostatic interactions has rendered the problem of peptide, protein, drug, and/or lipid protonation rather inaccessible, consequently deterring their study. However, the gradual raise of computational power, and the appearance of new and more refined force-fields, have made it possible to model the water/membrane region with increased realism.
The so-called constant-pH MD (CpHMD) methods aimed at solving the problem of including the pH effects in MD simulations by allowing protonable groups to periodically change their state during the simulation, thereby capturing the coupling between conformation and protonation. In our group, we are actively developing new CpHMD strategies that enable us to study the dynamic properties of solutes (peptides, proteins, or drugs) and lipid bilayers under different conditions of pH, ionic strength, redox potential and solvent composition.