Charge Transfer and Polarization in Solvated Proteins from Ab Initio Molecular Dynamics (original) (raw)

2011, The Journal of Physical Chemistry Letters

b S Supporting Information I t has been long recognized that water plays an important role in protein structure and dynamics. Water on the protein surface, often referred to as biological water, 1 is an essential element of protein interactions 2 and enzyme function. 3 Some water molecules reside in the same location near the protein surface for a long time 1 compared with the typical relaxation time under bulk conditions. These water molecules form strong hydrogen bonds 4 and can be directly observed in accurate model-free crystallographic experiments. 5 Classical force fields have made tremendous progress in describing interactions at proteinÀwater interfaces and can accurately predict such important energetic properties as solvation free energies of amino acids. 6,7 However, most of these theoretical models use a simplified "charged ball-and-spring" representation that is incapable of describing quantum mechanical phenomena like charge transfer (CT) and electronic polarization. Recently, it was demonstrated that CT effects account for approximately one-third of the binding energy in a neutral water dimer, 8 and for stronger H-bonds, one can anticipate this contribution to be even larger. Although CT and polarization effects are typically parametrized in classical force fields implicitly as a part of the electrostatic and Lennard-Jones two-body interactions, it remains an open question as to how accurately such approximations can describe biological water. Another recent study has stressed the importance of CT interactions in proteins and suggested this missing term should be explicitly included in future classical force field parametrizations. Although the effect of explicit solvent on protein structure and function has been studied for more than two decades, 4 solvated proteins have almost exclusively been treated using nonpolarizable classical force fields. Only a few attempts have been made to study proteinÀwater systems at higher levels of theory, such as semiempirical 10À12,35 or fragment molecular orbital 13 approaches. However, even these efforts have still relied on molecular dynamics (MD) simulations with classical force fields to provide atomic coordinates for higher level calculations. More rigorous treatment of solvated proteins by means of HartreeÀFock (HF) or density functional theory (DFT) methods is clearly needed. Ideally, one would use ab initio rather than classical MD trajectories in such calculations because classical and ab initio dynamics could potentially sample configurational space quite differently. In fact, DFT MD has been applied to study model systems such as solvated glycine dipeptide, 14 and substantial CT was observed in these simulations. However, to the best of our knowledge, ab initio (HF or DFT) MD has never been used to treat entire proteins. The major obstacle to the use of ab initio methods in this context is their high computational cost. Recent single-point energy calculations of solvated rubredoxin represent an illustrative example. 15 Calculation of the energy for the resulting 2825 atoms required over 1 h on 8196 processor cores. Dynamical simulations requiring hundreds or thousands of such calculations would appear to be completely out of reach. Fortunately, graphical processing units (GPUs) (essentially consumer videogame graphics cards) have emerged as a powerful alternative to traditional processors. We have redesigned algorithms for electronic structure theory and ab initio MD to leverage the strengths of GPUs, with promising results. 16À18 In this Letter, we ABSTRACT: Charge transfer at the Bovine pancreatic trypsin inhibitor (BPTI) proteinÀwater interface was analyzed by means of ab initio BornÀOppenheimer molecular dynamics simulation of the entire protein running on graphical processing units (GPUs). The efficiency of the GPU-based quantum chemistry algorithms implemented in our TeraChem program enables us to perform these calculations on a desktop computer. Mulliken and Voronoi deformation density (VDD) population analysis reveals that between 2.0 and 3.5 electrons are transferred from surrounding water molecules to the protein over the course of the 8.8 ps simulation. Solving for the electronic structure of BPTI in the absence of surrounding water molecules (i.e., in the gas phase) leads to large intraprotein charge transfer, where approximately one electron in total is transferred from neutral to polar residues. Solvation relieves this polarization stress, leading to a neutralization of the excess positive charge of the neutral residues.