Traditional implicit methods for modeling electrostatics in biomolecules use a two-dielectric

Traditional implicit methods for modeling electrostatics in biomolecules use a two-dielectric approach: a biomolecule is assigned low dielectric constant while the water phase is considered NSC 23766 as a high dielectric constant medium. 2013 Apr 9; 9(4): 2126-2136.). Here we examine various aspects of the modeling of polar solvation energy in such inhomogeneous systems in terms of the solute-water boundary and the inhomogeneity of the solute in the absence of water surrounding. The easy Gaussian-based dielectric function is usually implemented in the DelPhi finite-difference program and therefore the sensitivity of the results with respect to the grid parameters is usually investigated and it is shown LAMP1 that this calculated polar solvation energy is almost grid impartial. Furthermore the results are compared with the standard two-media model and it is exhibited that on average the standard method overestimates the magnitude of the polar solvation energy by a factor 2.5. Lastly the possibility of the solute to have local dielectric constant larger than of a bulk water is usually investigated in a benchmarking test against experimentally decided set of pKa’s and it is speculated that side chain rearrangements could result in local dielectric constant larger than 80. generated by atom is usually calculated as: (generated by atom is usually distance between and center of atom is the radius of atom defined by force filed used. Then the total atomic density is usually calculated as: (generated by the whole molecule; (is the reference dielectric value for biomolecules is the dielectric value for water. 2 Calculating polar component of solvation energy Currently DelPhi calculates the polar solvation energy in the case of sharp dielectric border(s) via the induced surface charges (reaction field energy) subroutine an approach which was repeatedly NSC 23766 shown to outperform the standard two steps methods 26. However the implementation of a similar approach in the case of easy dielectric boundary would require integration over the transition layer of NSC 23766 solute-bulk water. Currently this is computationally inefficient and because of that the two steps procedure was implemented. NSC 23766 This standard two steps method is usually implemented as follow: 1. A 3D dielectric distribution is usually calculated by using equation (1)-(3) and the grid energy of the system is usually calculated. 2. A Gaussian “surface” is usually constructed by selecting a certain epsilon value (such as epsilon=20). The epsilon values outside the surface are then set to have the value of vacuum while the epsilon distribution inside the surface stays the same as in step 1 1. The motivation for this is usually assumption at in vacuum the protein retains its properties. Then the grid energy of this new system is usually calculated as was set to be 4.0 and the variance was 0.93. These two parameters were optimized in our previous test on pKa calculations 15. The epsilon for surface cutoff is set to be =20 which is usually optimized from small molecule test 15. For the other parameters perfil is set as 70 salt concentration is usually 0 the scale is set as 2.0. The force field used is usually Amber 32. 4 Scale/resolution dependence To investigate the sensitivity of the results with respect to the grid resolution (scale) the following considerations were made: since the test cases are real proteins for which polar solvation energy cannot be calculate analytically one needs to define what the correct energy is usually. It is well known that an increase of the resolution (larger NSC 23766 scale) would result in more accurate results. Because of that the following measure of the accuracy was adopted: is the scale relative error at scale= is usually calculated and the scale was varied from 0.2 to 6.0 with step= 0.2. 5 Upper bound of dielectric constant inside biomolecule In the original equation (3) the upper bound of the dielectric constant of a biomolecule is the same as the dielectric constant value of water is the dielectric value for the entire biomolecule-water system. is the atomic density of the system. equal to 0 means the region is totally in water in this case the dielectric is set as > 0 or inside the biomolecule the upper bound of dielectric constant is set as = 4.0 and = 0.93) while the internal dielectric constant for the two-dielectric model was varied from 2.0 to 12.0 in steps of 2.0. Then the polar solvation energies.