We present the search for a new model of beta -factor XIIa, a blood coagulation enzyme, with an unknown experimental 3D-structure. We decided to build not one but three different models using different homologous proteins as well as different techniques and different modellers. Additional studies, including extensive molecular dynamics simulations on the solvated state, allowed us to draw several conclusions concerning homology modelling, in general, and beta -factor XIIa, in particular.

Molecular dynamics is a well-known technique very much used in the study of biomolecular systems. The trajectory files produced by molecular dynamics simulations are extensive, and the classical lossless algorithms give poor efficiencies in their compression. In this work, a new specific algorithm, named byte structure variable length coding (BS-VLC), is introduced. Trajectory files, obtained by molecular dynamics applied to trypsin and a trypsin:pancreatic trypsin inhibitor complex, were compressed using four classical lossless algorithms (Huffman, adaptive Huffman, LZW, and LZ77) as well as the BS-VLC algorithm. The results obtained show that BS-VLC nearly triplicates the compression efficiency of the best classical lossless algorithm, preserving a near lossless behavior. Compression efficiencies close to 50% can be obtained with a high degree of precision, and the maximum efficiency possible (75%), within this algorithm, can be performed with good precision.

In this work, molecular dynamics simulations have been used to study the transfer of some alkaline ions (Na+, K+, and Rb+), an alkaline-earth ion (Sr2+), and an organic ion (N(CH3)(4)(+)) across the water/2-heptanone liquid/liquid interface. Potentials of mean force were calculated and the ion transfer mechanisms were analyzed. The computed free energies of transfer exhibit a clear dependence on the ionic size and charge. In clear agreement with the experimental results obtained for several liquid/liquid biphasic systems, the free energies of transfer increase with the ionic charge and decrease with the ionic size. In all cases investigated, the potential of mean force for the transfer shows a monotonic increase in the Gibbs free energy as the ion progresses into the organic liquid. The major increase of the free energy occurs when the ion is on the organic side of the interface. The transfer seems to be an activationless process because there is no free energy barrier, this is true even in the case of the transfer of the organic ion. The transfer mechanism involves the formation of a water finger that connects the ions in the organic phase to the water phase during the transfer in both directions (i.e., from water to the organic phase and vice versa). For the organic and the alkaline ions, the water finger may be as long as 10 Angstrom and, for the alkaline-earth ion, as long as 14 Angstrom. In addition, it has been found that all the ions drag a part of their hydration shell into the organic phase, a phenomenon well documented experimentally. For similar ions, the number of water molecules and the fraction of the hydration shell dragged into the organic phase increased with the robustness of their shell. The N(CH3)(4)(+) ion drags slightly more water molecules than the alkaline ions, although the fraction of its hydration shell that remains in the organic solvent is much smaller. The mechanisms of the ion transfer processes studied here are all qualitatively similar, showing however a quantitative dependence on the ionic size and charge.

Molecular simulation methods such as molecular dynamics and Monte Carlo are fundamental for the theoretical calculation of macroscopic and microscopic properties of chemical and biochemical systems. These methods often rely on heavy computations, and one sometimes feels the need to run them in powerful massively parallel machines. For moderate problem sizes, however, a not so powerful and less expensive solution based on a network of workstations may be quite satisfactory. In the present work, the strategy adopted in the development of a parallel version is outlined, using the message passing model, of a molecular simulation code to be used in a network of workstations. This parallel code is the adaptation of an older sequential code using the Metropolis Monte Carlo method. In this case, the message passing interface was used as the interprocess communications library, although the code could be easily adapted for other message passing systems such as the parallel virtual machine. For simple systems it is shown that speedups of 2 can be achieved for four processes with this cheap solution. For bigger and more complex simulated systems, even better speedups might be obtained, which indicates that the presented approach is appropriate for the efficient use of a network of workstations in parallel processing.

A new method, based on the spatial decomposition of the reduced-density and pair-density matrices and the indistinguishable integrals formalism, is introduced to partition the molecular and stabilization energies into meaningful fragments. These are defined as entirely flexible variable-size entities, for example, atoms, group of atoms, ions, and interacting monomers. This new partitioning scheme is especially appropriated to study systems in which a directly bonded group-transfer process occurs. In these cases, the stabilization energies are partitioned into an intrafragment component, associated with the difference of intrinsic affinity to the transferred group between the involved fragments, and an interfragment component, associated with the difference of the magnitude of the interaction between the fragments in the initial and final binding complexes, This method was applied to the study of the arginine-carboxylate interactions, allowing us to have insight into what really happens in this system. Two (zwitterionic and neutral) binding complexes can be considered. The main effects accountable for the preferential stabilizations of the binding complexes are determined to be basis-set independent. The zwitterionic complex is favored by the interfragment component, while the neutral complex is favored by the larger intrinsic proton affinity of the acetate relatively to the methylguanidium. (C) 1999 John Wiley & Sons, Inc.

A theoretical study is presented on the influence of the interionic separation between the reacting metal cations on the kinetics of electron transfer reactions. The results of some simulations are presented to characterize the dependence of the activation free energy of the electron transfer process relatively to the interionic separation as well as the potential of mean force between the two cations considered in this study, Cu+ and Cu2+, in aqueous medium. The use of truncation of coulombic interactions is compared with the: use of Ewald sums in the treatment of long range interactions. The truncation of coulombic interactions in the simulations is observed to have a strong influence in the final results.

We are interested in modeling enzyme-inhibitor interactions with a view to improve the understanding of the biology of these processes. The present work focuses, therefore, on the research on enzyme-inhibitor interactions using two highly homologous enzymes as our models: beta-factor XIIa and trypsin. This study so far has focused on the following: (1) arginine-carboxylate interactions such as the one occurring in the "binding pocket" of beta-factor XIIa with an inhibitor; according to the present calculations, the neutral form is usually more stable than is the zwitterion in hydrophobic environments as in the case of the above-mentioned complex. (2) Interactions present in the contact region between trypsin and PTI; the contribution of some amino acids of that region to the binding energy of the complex trypsin-PTI was determined using free-energy simulation methods. (3) Interactions involved in the inhibition of trypsin by PTI; hybrid quantum-classical mechanical calculations (LSCF) were performed to further this point. (C) 1994 John Wiley & Sons, Inc.