During the photocycle of photoactive yellow protein (PYP), the pK(a) values of the chromophore (S-methyl p-coumarate) and Glu46 undergo drastic changes. In the dark state (pG), the chromophore is deprotonated and Glu46 is protonated. In the blue-shifted intermediate called pB, their protonation states are inverted. These pK(a) changes are thought to be closely related to the mechanism of signal transduction leading to bacterial phototaxis. In this study, we investigate the physical origin of the above pK(a) shifts using quantum chemical calculations at the level of ab initio Hartree-Fock (HF), semiempirical AMI, and density functional theory (DFT). Here, S-methyl p-coumarate and acetic acid (propionic acid) are chosen as models of the chromophore and Glu46, respectively. First, the protein environment surrounding these residues is approximated by a dielectric continuum. The HF and DFT calculations coupled with a continuum solvent model (SCIPCM or COSMO) reveal that the relative pK(a) (DeltapK(a)) of acetic acid to the chromophore model has a positive value in low dielectric media, meaning that the chromophore is deprotonated and the acetic acid is protonated. However, with increasing dielectric constant (epsilon), the DeltapK(a) value gradually decreases and its sign is inverted from plus to minus at about epsilon = 2-4. Consequently, in higher dielectric media (4 < epsilon), the chromophore is protonated and Glu46 is deprotonated. To obtain more detailed information about the mechanism of the DeltapK(a) shifts, we perform hybrid quantum mechanics/molecular mechanics (QM/MM) calculations in which the chromophore and Glu46 are treated quantum chemically and the protein environment is approximated by an assembly of partial atomic charges, obtained from linear-scaling molecular orbital calculations (known as MOZYME) for the entire PYP. These calculations also indicate that the sign of the DeltapK(a), is inverted from plus to minus on going from pG to pB. Also, detailed analysis indicates that this inversion is mainly caused by the effect of slight conformational differences between pG and pB, as observed by X-ray crystallographic studies.