Study on the structure of water molecules in human ras oncogene proteins and the thermodynamics of water clusters

Abstract

To investigate the behavior of water molecules in the catalytic sites of human ras p21 proteins, we have performed HDMC simulations on the hydrated ras p21 proteins of various forms; the normal ras complexed with GDP (normal-p21/GDP), the mutant ras complexed with GDP (mutant-p21/GDP), and the normal ras complexed with GTP (normal-p21/GTP). And also we have performed MMC on the normal-p21/GDP system. Comparison between HDMC and MMC shows the improved efficiency of HDMC on this complicated system. Interaction between water molecules is represented by the TIP3P potential function. The solute (protein or GDP/GTP)-water interaction is represented by the Coulomb and van der Waals interactions from CHARMM force field spliced with TIP3P. We have reported the mean square displacement, dipole correlation function, the distribution of small water clusters connected by the hydrogen-bonded circular network, and the average lengths and fluctuations of hydrogen bonds between water molecules and atoms of solute. Water molecules form different local structures in different types of the protein-GDP (GTP) complexes. The distribution of structural water in normal-p21/GDP is localized over narrow range compared with the other two systems. The mutant-p21/GDP system is less stabilized than the normal systems in energy or hydrogen bond. The relaxation of local hydrogen bond network of mutant system is faster than those of other systems. In GTP complex, we detected the water molecule to act as the attacking nucleophile in GTP hydrolysis and calculated the average hydrogen bond length and its fluctuation. This water molecule is stabilized and highly polarized by the hydrogen bond with protein atoms. We have carried out molecular dynamic simulations on water clusters of various sizes and temperatures. For a systematic study, we have constructed the clusters by successive addition of molecular layers around a 5-molecule cluster up to 183 molecules. The simulations have been also performe...