Progress toward chemical accuracy in the computer simulation of condensed phase reactions.

We describe a procedure for the generation of chemically accurate computer-simulation models to study chemical reactions in the condensed phase. The process involves (i) the use of a coupled semiempirical quantum and classical molecular mechanics method to represent solutes and solvent, respectively; (ii) the optimization of semiempirical quantum mechanics (QM) parameters to produce a computationally efficient and chemically accurate QM model; (iii) the calibration of a quantum/classical microsolvation model using ab initio quantum theory; and (iv) the use of statistical mechanical principles and methods to simulate, on massively parallel computers, the thermodynamic properties of chemical reactions in aqueous solution. The utility of this process is demonstrated by the calculation of the enthalpy of reaction in vacuum and free energy change in aqueous solution for a proton transfer involving methanol, methoxide, imidazole, and imidazolium, which are functional groups involved with proton transfers in many biochemical systems. An optimized semiempirical QM model is produced, which results in the calculation of heats of formation of the above chemical species to within 1.0 kcal/mol (1 kcal = 4.18 kJ) of experimental values. The use of the calibrated QM and microsolvation QM/MM (molecular mechanics) models for the simulation of a proton transfer in aqueous solution gives a calculated free energy that is within 1.0 kcal/mol (12.2 calculated vs. 12.8 experimental) of a value estimated from experimental pKa values of the reacting species.

Computer speech synthesis: its status and prospects.

Computer speech synthesis has reached a high level of performance, with increasingly sophisticated models of linguistic structure, low error rates in text analysis, and high intelligibility in synthesis from phonemic input. Mass market applications are beginning to appear. However, the results are still not good enough for the ubiquitous application that such technology will eventually have. A number of alternative directions of current research aim at the ultimate goal of fully natural synthetic speech. One especially promising trend is the systematic optimization of large synthesis systems with respect to formal criteria of evaluation. Speech recognition has progressed rapidly in the past decade through such approaches, and it seems likely that their application in synthesis will produce similar improvements.

Computer determination of peptide conformations in water: different roads to structure.

Fragments of proteins (short peptides) that "fold" suggest a mechanism of how complete conformational search in protein folding is avoided. We used a computational method to determine structures of two foldable peptides in explicit water: RVEW and CSVTC. The optimization starts from random structures and no experimental constraints are used. In agreement with NMR data, the simulations find a hydrophobic pair (Val/Trp) in REVW. The structure of CSVTC is induced by a surface water that bridges two amide hydrogens, a drive to structure hypothesized by Ben-Naim [Ben-Naim, A. (1990) J. Chem. Phys. 93, 8196-8210] that is largely ignored in studies of folding. Tendency to structure in short peptide chains suggests a mechanism for the formation of short-range nucleation sites in protein folding.

Simulating spin systems on IANUS, an FPGA-based computer

We describe the hardwired implementation of algorithms for Monte Carlo simulations of a large class of spin models. We have implemented these algorithms as VHDL codes and we have mapped them onto a dedicated processor based on a large FPGA device. The measured performance on one such processor is comparable to O(100) carefully programmed high-end PCs: it turns out to be even better for some selected spin models. We describe here codes that we are currently executing on the IANUS massively parallel FPGA-based system.