Bovine pancreatic trypsin inhibitor simulations

M. H. Hao, M. R. Pincus, S. Rackovsky, and H. A. Scheraga. Unfolding and refolding of the native structure of bovine pancreatic trypsin inhibitor studied by computer simulations. Biochemistry, 32 9614-9631, 1993. 

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]. 

M Vasquez, ElA Scheraga. Calculation of protein conformation by the build-up procedure. Application to bovine pancreatic trypsin inhibitor using limited simulated nuclear magnetic resonance data. J Biomol Struct Dyn 5 705-755, 1988. 

The details of many all-atom unfolding simulation studies have been summarized in several reviews [17,46,47]. These studies include unfolding simulations of a-lactalbumin, lysozyme, bovine pancreatic trypsin inhibitor (BPTI), barnase, apomyoglobin, [3-lacta-mase, and more. The advantage of these simulations is that they provide much more detailed information than is available from experiment. However, it should be stressed that there is still only limited evidence that the pathways and intermediates observed in the nanosecond unfolding simulations correlate with the intermediates observed in the actual experiments. 

Bovine Pancreatic Trypsin Inhibitor (BPTI) Simulations... 

We extrapolate from two simulations, the 10 ps simulation on bovine pancreatic trypsin inhibitor (BPTI) reported over twenty years ago [61] and the recent 1 gs simulation on the villin headpiece subdomain. [9] Each of these was a state-of-the-art simulation, using the best algorithms and the most powerful hardware available at the time. 

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... 

Another globular protein, bovine pancreatic trypsin inhibitor (BPTI), has also been treated by the build-up procedure however, because of a limitation on computer time when the calculation on this protein was carried out, a limited set of simulated NMR distance constraints (taken from the known X-ray structure225) was used226-227 to reduce the number of conformations... 

M. Vasquez and H. A. Scheraga, J. Biomol. Struct. Dyn., 5, 70S (1988). Calculation of Protein Conformation by the Build-up Procedure. Application to Bovine Pancreatic Trypsin Inhibitor Using Limited Simulated Nuclear Magnetic Resonance Data. 

Verification of the structural and dynamic behavior of proteins predicted by simulations has been possible by comparison with experiment. Approximate agreement between the average structure obtained in the first simulation of a protein (McCammon et al. 1977), that of bovine pancreatic trypsin inhibitor (BPTI), and the... 

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. 

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-... 

In an analysis of the correlation function Pi (see Eq. 110) for the internal motions of the four tyrosines in the bovine pancreatic trypsin inhibitor in a van der Waals solvent,193 it was found that for three out of four tyrosines the correlation function P2 decays from its initial value of unity to a plateau value of 0.8 in less than 2 ps and then remains essentially constant for the rest of the simulation for the fourth tyrosine (Tyr 10), which is on the surface of the... 

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]. 

The simulations reported in the paper dealt with bovine pancreatic trypsin inhibitor (BPTI), a small (58 amino acid) protease inhibitor whose structure is stabilized by three disulfide crosslinks. The simulation began with a set of X-ray coordinates and zero velocities, and ran 100 steps of numerical integration of Newton s equations of motion, with each time step being about 1 fs. Since the X-ray coordinates did not correspond to a minimum of... 

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