Quantitative modeling of stochastic systems in molecular biology by using stochastic Petri nets

An integrated understanding of molecular and developmental biology must consider the large number of molecular species involved and the low concentrations of many species in vivo. Quantitative stochastic models of molecular interaction networks can be expressed as stochastic Petri nets (SPNs), a mathematical formalism developed in computer science. Existing software can be used to define molecular interaction networks as SPNs and solve such models for the probability distributions of molecular species. This approach allows biologists to focus on the content of models and their interpretation, rather than their implementation. The standardized format of SPNs also facilitates the replication, extension, and transfer of models between researchers. A simple chemical system is presented to demonstrate the link between stochastic models of molecular interactions and SPNs. The approach is illustrated with examples of models of genetic and biochemical phenomena where the UltraSAN package is used to present results from numerical analysis and the outcome of simulations.

Large vortex-like structure of dipole field in computer models of liquid water and dipole-bridge between biomolecules

We propose a framework to describe the cooperative orientational motions of water molecules in liquid water and around solute molecules in water solutions. From molecular dynamics (MD) simulation a new quantity “site-dipole field” is defined as the averaged orientation of water molecules that pass through each spatial position. In the site-dipole field of bulk water we found large vortex-like structures of more than 10 Å in size. Such coherent patterns persist more than 300 ps although the orientational memory of individual molecules is quickly lost. A 1-ns MD simulation of systems consisting of two amino acids shows that the fluctuations of site-dipole field of solvent are pinned around the amino acids, resulting in a stable dipole-bridge between side-chains of amino acids. The dipole-bridge is significantly formed even for the side-chain separation of 14 Å, which corresponds to five layers of water. The way that dipole-bridge forms sensitively depends on the side-chain orientations and thereby explains the specificity in the solvent-mediated interactions between biomolecules.

A two-year experience teaching computer literacy to first-year medical students using skill-based cohorts

Because it is widely accepted that providing information online will play a major role in both the teaching and practice of medicine in the near future, a short formal course of instruction in computer skills was proposed for the incoming class of students entering medical school at the State University of New York at Stony Brook. The syllabus was developed on the basis of a set of expected outcomes, which was accepted by the dean of medicine and the curriculum committee for classes beginning in the fall of 1997. Prior to their arrival, students were asked to complete a self-assessment survey designed to elucidate their initial skill base; the returned surveys showed students to have computer skills ranging from complete novice to that of a systems engineer. The classes were taught during the first three weeks of the semester to groups of students separated on the basis of their knowledge of and comfort with computers. Areas covered included computer basics, e-mail management, MEDLINE, and Internet search tools. Each student received seven hours of hands-on training followed by a test. The syllabus and emphasis of the classes were tailored to the initial skill base but the final test was given at the same level to all students. Student participation, test scores, and course evaluations indicated that this noncredit program was successful in achieving an acceptable level of comfort in using a computer for almost all of the student body.

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.