Microscopic simulations of macroscopic dielectric constants of solvated proteins

Abstract

Microscopic simulation of solvated proteins are used to evaluate the relationship between the macroscopic field and macroscopic polarization, thus providing the corresponding dielectric constant, E. This parameter is evaluated by two different methods which are first examined and calibrated by calculating the dielectric constant of bulk water. These calculations indicate that the reaction field, which represents the effect of the missing solvent around the given explicit region, must be included in the simulations in order to obtain a reasonable value for E. The corresponding effect is not related to the reduction of the effective interactions between charges in the reference region but to the intrinsic value ofE in that region. This means that vacuum calculations ofE in proteins might underestimate its actual value. Or in other words, calculations of E in proteins must include the effect of the reaction field or a sufficiently large number of surrounding solvent molecules. Having included the surrounding solvent in simulations of trypsin, we find that E depends on the actual protein site. In particular, we find that E can be as large as 10 in sites of catalytic importance. It is pointed out that the dielectric constant that should be used in calculations of protein properties depends on the part of the system which is not treated explicitly and is not necessarily the macroscopic E. For example, using E in electrostatic calculations that consider the protein polar groups explicitly accounts twice for some aspects of the protein polarity. Finally, possible ways to use microscopically determined dielectric constants for electrostatic calculations in protein are considered.

Chemical Rescue of Phosphoryl Transfer in a Cavity Mutant: A Cautionary Tale for Site-Directed Mutagenesis,

“…Methanol, ethanol, and propanol react 6-40-fold more slowly than water, despite their similar reactivities in solution and their small size relative to the size of the cavity. The 4 As represented in the reaction in the text, ATP is also subsaturating in these experiments. Nevertheless the same relative reactivities for subsaturating alcohols would hold with saturating ATP (E‚ATP + ROH f [E‚ATP‚ROH] ‡ ), as the reaction step: E + ATP + ROH f E‚ATP + ROH is independent of the alcohol (see also footnote 2).…”

Development of constant-pH simulation methods in implicit solvent and applications in biomolecular systems

“…This sphere is immersed in a medium with high dielectric permittivity ( s ), the electrolyte solution. At this point, proposing a dielectric interface, they introduced a rather polemical and controversial model choice under intense debate in the literature (Demchuk and Wade 1996;Penfold et al 1998;Warshel andÅqvist 1991;King et al 1991;Antonsiewicz et al 1994Antonsiewicz et al , 1996Simonson and Perahia 1995;Simonson and Brooks 1996;Löffler et al 1997;Sham et al 1997;Warwicker 1999 A dielectric constant is a macroscopic parameter related to the movement of microscopic charges. It describes the reorientation of the electronic cloud around a nucleus and/or the reorientation of permanent dipoles in the presence of an electric field (Böttcher 1973).…”

Dielectric relaxation of cytochrome c oxidase: Comparison of the microscopic and continuum models

“…The nonlinear effects in the medium which include water were observed in many earlier studies. 16,23,24,27,34,38 In our system, the effect is mainly due to reorientation of one particular water molecule located between the two propionates of heme a 3 ; this water molecule forms different types of hydrogen bonds with His291 in its protonated and deprotonated states, and in the process of charging needs to change orientation. The orientation flipping of that water molecule occurs around = 0.75, which apparently breaks the linearity of the response, see Fig.…”

“…A similar approach was used earlier to study dielectric relaxation in several other proteins. 10,14,15,17,[23][24][25] We apply this strategy to examine deprotonation of His291 ligand of Cu B metal center of CcO ͑in bovine heart cytochrome c oxidase͒. This residue is a key element of a recently proposed proton pumping mechanism of the enzyme.…”

“…In low-dielectric environments, such as interior of a protein, the standard MD approach produces poor results; therefore, the missing electronic polarization, the cause of the problem, needs to be treated explicitly. [31][32][33] Another problem is that in many cases, especially when the polarizable medium includes water, the microscopic dielectric response ͑or relaxation͒ of the system can be nonlinear 16,23,24,27,34 while the continuum models assume linearity of the dielectric response. The computation analysis presented in this work addresses both of the above problems.…”