Robert F. Goldstein

MOIL: A program for simulations of macromolecules

Abstract A package of computer programs for molecular dynamics simulations-MOIL-is described. A flexible data structure enables the study of macromolecules with potentials consistent with the AMBER/OPLS force field. The supplied parameter set has proteins in mind. In addition to ‘wide spread’ applications such as energy, energy minimization, normal modes, dynamics and free energy calculations code is also provided to pursue less common applications. This includes reaction path calculations (in condensed phases), uses of the mean field approach for enhanced sampling (LES-locally enhanced sampling) and calculations of curve crossing using the Landau-Zener model. A brief review of the overall program is provided. A few modules are discussed in considerable detail.

Structure‐based analysis of the initial electron transfer step in bacterial photosynthesis: Electric field induced fluorescence anisotropy

The fluorescence intensity from randomly oriented, immobilized Rb. sphaeroides reaction centers at 77 K increases in the presence of an externally applied electric field. We have proposed that this increase is due to a net decrease in the rate of the forward electron transfer reaction which competes with the prompt fluorescence. This decrease results from the change in the free energy difference between the reactant and very dipolar product state in the presence of the electric field. Because the free energy change and thus the electron transfer rate for a given reaction center depends on its orientation relative to the field, the intensity of the competing fluorescence likewise becomes orientation dependent. An expression is derived relating the degree of this electric field induced fluorescence anisotropy to the angle ζet between the fluorescence transition moment and the effective dipole moment whose interaction with the field results in the change in the rate of the electron transfer reaction which co...

Studies of DNA dumbbells VII: Evaluation of the next-nearest-neighbor sequence-dependent interactions in duplex DNA

Melting experiments were conducted on 22 DNA dumbbells as a function of solvent ionic strength from 25–115 mM Na+. The dumbbell molecules have short duplex regions comprised of 16–20 base pairs linked on both ends by T4 single‐strand loops. Only the 4–8 central base pairs of the dumbbell stems differ for different molecules, and the six base pairs on both sides of the central sequence and adjoining loops on both ends are the same in every molecule. Results of melting analysis on the 22 new DNA dumbbells are combined with our previous results on 17 other DNA dumbbells, with stem lengths containing from 14–18 base pairs, reported in the first article of this series (Doktycz, Goldstein, Paner, Gallo, and Benight, Biopoly 32, 1992, 849–864). The combination of results comprises a database of optical melting parameters for 39 DNA dumbbells in ionic strengths from 25–115 mM Na+. This database is employed to evaluate the thermodynamics of singlet, doublet, and triplet sequence‐dependent interactions in duplex DNA. Analysis of the 25 mM Na+ data reveals the existence of significant sequence‐dependent triplet or next‐nearest‐neighbor interactions. The enthalpy of these interactions is evaluated for all possible triplets. Some of the triplet enthalpy values are less than the uncertainty in their evaluation, indicating no measurable interaction for that particular sequence. This finding suggests that the thermodynamic stability of duplex DNA depends on solvent ionic strength in a sequence‐dependent manner. As a part of the analysis, the nearest‐neighbor (base pair doublet) interactions in 55, 85, and 115 mM Na+ are also reevaluated from the larger database.

HTML to the max: a manifesto for adding SGML intelligence to the World-Wide Web

Abstract HTML demonstrates that SGML markup is useful for networked information. How can it be made even more useful? One way is to extend the tag set from HTML to HTML2, etc. We argue here for a more radical approach: full SGML awareness in WWW. We believe the difficulties are small, the cost affordable, and the advantages overwhelming. SGML is a metalanguage for defining markup languages; HTML is just one instance of this infinite family. At present, documents in other SGML document types must be translated into HTML for display by a Mosaic client—sometimes this imposes unacceptable information loss. WWW browsers could handle other SGML document types without translation by launching a general-purpose SGML browser to view them, as they now launch graphics viewers; a better solution overall would be to build SGML display into the WWW browsers themselves. Either way, display of an SGML document would be controlled by a style sheet using a small number of display primitives (“bold”, “line break”, etc.) to specify the rendition of each element type. For “well-known” document type definitions (DTDs) like HTML, style sheets could be distributed with the browser, or built in. For other DTDs, the browser would fetch a style sheet from the server. Using style sheets, browser software can also make it easy to customize document display. DTDs and style sheets can be designed to accommodate extensions, ensuring that authors can make small extensions to the tag set with no change whatsoever in the target browsers and virtually no performance penalty.

Do vibrational spectroscopies uniquely describe protein dynamics? The case for myoglobin.

We develop a quasi-harmonic description of protein dynamics and apply this description to the anomalous Mössbauer, infrared, x-ray diffraction, and EXAFS (extended x-ray absorption fine structure spectroscopy) data that are available for myoglobin (Mb) and its interactions with carbon monoxide (CO). In the quasi-harmonic approximation the dynamical parameters derived from these spectroscopic data are relevant in the calculation of reaction rates, and we give a quantitative description of the nonexponential kinetics of Mb-CO binding observed at low temperatures. All these data have previously been interpreted in terms of the more complex conformational substates model for protein dynamics. We point out several problems with this model and propose experiments that can provide detailed tests of the quasi-harmonic theory proposed here.

Macromolecular diffusion constants: a calculational strategy

Calculations of diffusion constants for rigid molecules of arbitrary shape are often based on hydrodynamic interactions between freely moving spheres. Molecules can be modeled as collections of spheres, and the interactions are approximated as pairwise additive. Singularities previously associated with nearly linear geometries and with geometries dominated by a large central element can be avoided by including torque‐angular velocity and torque‐velocity coupling, as well as the usual force‐velocity coupling between spheres. I provide explicit formulas for these couplings for both nonoverlapping and overlapping spheres, and also show how to include effects of one sphere on the self‐diffusion of another. This formulation is incorporated in an algorithm that involves neither Gauss–Seidel iterations nor direct inversion of a large matrix.

EQUIL: Simulation and data analysis of binding reactions with arbitrary chemical models

We have developed an algorithm for simulation and analysis of arbitrary chemical systems in equilibrium, with emphasis on ligand binding reactions. The program EQUIL can treat reactions involving multiple ligands, multiple binding sites, ternary complex models, allosteric effectors, competitive and noncompetitive binding, conformational changes, cooperativity, and generally any scheme that can be represented as a set of chemical equations. EQUIL is based on a general thermodynamic model of chemical equilibria; it does not involve nonlinear transformation of experimental data, but it does require the user to define the model of interaction between ligands and receptors by writing down the appropriate chemical reactions. EQUIL contains features of particular importance to ligand binding experiments: variable binding capacities, nonspecific binding, and the ability to simultaneously analyze data from different types of experiments. Furthermore, the simulation feature of EQUIL allows the user to investigate the feasibility of experiments that could possibly distinguish between different reaction models. We illustrate the use of this program on personal computers to analyze and simulate simple and complicated interactions between ligands and receptors.

Moil: A Molecular Dynamics Program with Emphasis on Conformational Searches and Reaction Path Calculations

The field of computational biology has expanded considerably in the last few years. Insight to the dynamics of biomolecules, the design of new drugs and the interactions that lead to stability of macromolecules has been obtained. Crucial in bringing these changes was the introduction of “user friendly” computer programs so that the number of potential users expanded considerably. It is now possible to visualize complex molecules and to study their structure and thermodynamics properties. The strength of this approach and what makes it so attractive is the possibility of studying the behavior of a variety of molecules using essentially the same set of tools. Constructing a large number of molecules was made possible by the use of a data base of molecular pieces: Different molecules are described using common fragments. For example, all proteins are constructed from the same monomers — amino acids. Another example of repeating fragments is found in the base-pairs of DNA. The fragment solution is chemically intuitive, however, it is approximate. In general the intramolecular interactions in an amino acid are influenced by its neighborhood. For example the charge distribution is determined not only by the identity of the amino acid (as is usually assumed) but also by the solvent, the nearby amino acids and the specific conformation of the fragment. Nevertheless, this approximate approach has a number of successes that are documented in the literature1 and therefore not covered in this manuscript.

Simple Models for the Dynamics of Biomolecules: How Far Can We Go?

Biological macromolecules exhibit a remarkable variety of dynamical phenomena. As experimental methods for characterizing these phenomena have improved in the last decade, two theoretical questions have been brought into focus: To what extent are the observed dynamics relevant to biological function?, and Can we develop a simple physical picture of the functionally important dynamics?

Biomolecular Dynamics — Quantum or Classical? Results for Photosynthetic Electron Transfer

We discuss the relations between quantum and classical descriptions of the atomic motions which accompany electron transfer reactions. Rather than arguing that a specific model is required to account for some particular observations, we show that a broad class of models can be qualitatively understood, and that is possible to understand the mechanism of quantum/classical crossover without discussing details of a particular model. We then motivate the hypothesis that the photosynthetic reactions operate in the quantum regime of these models. This hypothesis has several robust consequences which are confirmed by recent experiments.