This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The purpose of this study is to determine the pKa of sphingosine 1-phosphate (S1P) when bound to a G Protein Coupled Receptor (GPCR), in order to better understand S1P-receptor interactions. Such understanding may contribute to development of models of agonists for the GPCR, which may have potential as future drugs. We previously derived models for the interaction of S1P with the S1P1 receptor, a GPCR family member receptor, using homology modeling and molecular mechanics. However, the charge and pKa of the S1P phosphate are unknown in the binding environment of S1P1. The binding environment contains two arginine, a lysine, an isoleucine, a tryptophan and glutamic acid residues. We will compute the pKa of the S1P phosphate in S1P1, by using the program GAMESS. The pKa determination is based on the free energy G of the proton exchange reaction: HA(aq) + R-(aq) A-(aq) + RH(aq) by the equation pKa = 5.66 + G/1.36 = 5.66 + {[G(A-) G(HA)] [G(R-) G(RH)]}/1.36 Here, 5.66 is the experimental pKa value of O-phosphoethanolamine (R) at 298K, and A is S1P in the S1P1 receptor. The value 1.36 is RTln10 at the same temperature in kilocalories per mol. Each free energy term is a sum of solvation free energy and electronic energy. The electronic energy is composed of the potential energy of the electrons and nuclei and the kinetic energy of the electrons, and will be calculated using quantum mechanical technique [MP2/6-3+G(2d,p)]. The solvation energy will be calculated by the polarized continuum model (PCM)*, which represents the solvent as a continuum surrounding the solute. We will optimize the structure, by minimizing the total energy with a recently developed algorithm**, which includes solvation energy calculation, and therefore optimize the free energy at the level PCM/RHF/6-31G(d). Diffuse functions will be added to all heavy atoms in negatively charged groups, and the UAHF radii will define the molecular cavities. Reference: * Cances E, Mennucci B, Tomasi J. A new integral equation formalism for the polarizable continuum model: theoretical background and applications to isotropic and anisotropic dielectrics. J Chem Phys 1997; 107(8):3032-3041 ** Li H and Jensen J H. Improving the efficiency and convergence of geometry optimization with the polarizable continuum model: new energy gradients and molecular surface tessellation. J Comp Chem 2004; 25(12):1449-62
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