Pancreatic trypsin inhibitor, molecular

Niedermeier, C. and K. Schulten. (1992). Molecular-dynamics simulations in Heterogeneous Dielectric and Debye-Huckel Media Application to the Protein Bovine Pancreatic Trypsin-inhibitor. Molecular Simulation. 8 361-387. 

As examples of applications, we present the overall accuracy of predicted ionization constants for about 50 groups in 4 proteins, changes in the average charge of bovine pancreatic trypsin inhibitor at pH 7 along a molecular dynamics trajectory, and finally, we discuss some preliminary results obtained for protein kinases and protein phosphatases. 

In periodic boimdary conditions, one possible way to avoid truncation of electrostatic interaction is to apply the so-called Particle Mesh Ewald (PME) method, which follows the Ewald summation method of calculating the electrostatic energy for a number of charges [27]. It was first devised by Ewald in 1921 to study the energetics of ionic crystals [28]. PME has been widely used for highly polar or charged systems. York and Darden applied the PME method already in 1994 to simulate a crystal of the bovine pancreatic trypsin inhibitor (BPTI) by molecular dynamics [29]. 

Using this approach, Bizzozero and Zweifel (9) and Bizzozero and Dutler (10) have constructed molecular models of two intermediates (an enzyme-substrate complex and a tetrahedral intermediate) by appropriate modification of the models of stable enzyme-species. The stable enzyme-species used (15, 16) are trypsin-benzamidine complex (TR-B) (17), trypsin-pancreatic trypsin inhibitor complex (TR-PTI) (18, 19) and tosyl-chymotrypsin (Tos-CHT) (20) which are related to enzyme substrate complex, tetrahedral intermediate and acyl-enzyme respectively. 

Because of the ease with which molecular mechanics calculations may be obtained, there was early recognition that inclusion of solvation effects, particularly for biological molecules associated with water, was essential to describe experimentally observed structures and phenomena [32]. The solvent, usually an aqueous phase, has a fundamental influence on the structure, thermodynamics, and dynamics of proteins at both a global and local level [3/]. Inclusion of solvent effects in a simulation of bovine pancreatic trypsin inhibitor produced a time-averaged structure much more like that observed in high-resolution X-ray studies with smaller atomic amplitudes of vibration and a fewer number of incorrect hydrogen bonds [33], High-resolution proton NMR studies of protein hydration in aqueous... 

Brunne, R. M., and Van Gunsteren, W. F. (1993) D5mamical properties of bovine pancreatic trypsin inhibitor from a molecular dynamics simulation at 5000 atm, FEBSLetters 323, 215-217... 

To illustrate the solvent effect on the average structure of a protein, we describe results obtained from conventional molecular dynamics simulations with periodic boundary conditions.92,193 This method is well suited for a study of the global features of the structure for which other approaches, such as stochastic boundary simulation methods, would not be appropriate. We consider the bovine pancreatic trypsin inhibitor (BPTI) in solution and in a crystalline environment. A simulation was carried out for a period of 25 ps in the presence of a bath of about 2500 van der Waals particles with a radius and well depth corresponding to that of the oxygen atom in ST2 water.193 The crystal simulation made use of a static crystal environment arising from the surrounding protein molecules in the absence of solvent. These studies, which were the first application of simulation methods to determine the effect of the environment on a protein, used simplified representations of the surround-... 

Recent progress in X-ray diffraction of protein crystals in the diamond anvil cell will also make it possible to obtain quantitative information on the cavities [42, 43]. Optical spectroscopy [44] and neutron scattering [45] should also be valuable tools to probe the role of cavities. High-pressure molecular dynamics simulations should also allow estimating the contributions of the hydration and the cavities. High-pressure simulations on the small protein, bovine pancreatic trypsin inhibitor, indicate an increased insertion of water into the protein interior before unfolding starts to occur [46,47]. 

Brunne, R.M., Liepinsh, E., Otting, G., Wuthrich, K., and Vangunsteren, WF. (1993) Hydration of proteins a comparison of experimental residence times of water-molecules solvating the bovine pancreatic trypsin-inhibitor with theoretical-model calculations. Journal of Molecular Biology, 231, 1040-1048. 

Ttichsen, E., Woodward, C. (1985) Mechanism of surface peptide proton exchange in bovine pancreatic trypsin inhibitor salt effects and O-protonation. Journal of Molecular Biology, 185 (2), 421 30. 

Simulations of BPTI (bovine pancreatic trypsin inhibitor) in van der Waals solvents have been reported [74, 75], the density and molecular size were chosen to simulate those of water. More realistic water representations were used in further simulations [18, 76, 77]. Avian pancreatic polypeptide hormone in crystal and in aqueous solution has been reported by Kruger [78]. These studies tend to indicate that the calculations in vacuo represent fairly correctly the motion of the protein core, while exposed sidechains react more strongly to solvent effects. 

Vrbka L, Jungwirth P, Bauduin P, Touraud D, Kunz W (2006) Specific itm effects at protein surfaces a molecular dynamics study of bovine pancreatic trypsin inhibitor and horseradish peroxidase in selected salt solutions. J Phys Chem B 110 7036-7043... 

McCammon et al. have simulated the molecular dynamics of a globular protein molecule, bovine pancreatic trypsin inhibitor, and the water strongly bound to it, to provide, since the rich variety of motions at ordinary temperatures is indicated, an improved picture in comparison to the crystal structure. Fluctuations in some rotation angles tend to correlate with others, thus conserving overall structure, but large scale concerted motions are also demonstrated. The structure of water around lysozyme (EC 3.2.1.17) has been investigated by the Metropolis method, all molecules of the crystal structure being present, ... 

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