Design of a reduced point charge model for proteins: Applications to molecular electrostatic potential and solvation energy calculations

To model and simulate large molecular systems like proteins, the development of reduced representations is currently an active field of research. In a previous work [1], we developed an approach to locate minima and maxima in a smoothed molecular electrostatic potential (MEP) Φ, and applied it to the design of amino acid (AA) reduced point charge models (Fig. left). Such models were then used for the evaluation of the MEP of KcsA, a potassium ion channel structure. While efficient in approximating the corresponding all-atom MEP, the models however present two drawbacks. First, the points are located away from the skeleton of the structure, and second, their location and charge value may be dependent on the AA conformation.
In the present work, the approach is modified so as to determine the point charge centers from electron density (ED) distribution functions ρsm obtained using the Poisson equation:

Such a new procedure allows to overcome the two drawbacks mentioned above when extrema of ρ are located in distributions built on negative and positive charges separately (Fig. right). In this work, the charge values allowing the calculation of the initial MEP Φ are taken from the AMBER99 force field [2]. The new AA models allow to reproduce protein MEP maps, and additionally, provide solvation free energies obtained using the program APBS [3] that are in better agreement with the all-atom ones. Calculations were achieved on a set of 53 protein structures, listed in [4], and four KcsA channel structures (PDB access codes 1BL8, 2ATK, 2P7T, and 1S5H).

1. L. Leherte, D.P. Vercauteren, J. Chem. Theory Comput. 5 (2009) 3279-3298
2. J. Wang, P. Cieplak, P.A. Kollman, J. Comput. Chem. 21 (2000) 1049-1074
3. N.A. Baker, D. Sept, S. Joseph, M.J. Holst, J.A. McCammon, Proc. Natl. Acad. Sci. USA 98 (2001) 10037-10041
4. H. Tjong, H.-X. Zhou, J. Chem. Theory Comput. 4 (2008) 507-514