Simulation vs. Understanding: A Tension,in Quantum Chemistry and Beyond. Part B. The March of Simulation,for Better or Worse

In the second part of this Essay, we leave philosophy, and begin by describing Roald's being trashed by simulation. This leads us to a general sketch of artificial intelligence (AI), Searle's Chinese room, and Strevens’ account of what a go‐playing program knows. Back to our terrain—we ask “Quantum Chemistry, ? ca. 2020?” Then we move to examples of Big Data, machine learning and neural networks in action, first in chemistry and then affecting social matters, trivial to scary. We argue that moral decisions are hardly to be left to a computer. And that posited causes, even if recognized as provisional, represent a much deeper level of understanding than correlations. At this point, we try to pull the reader up, giving voice to the opposing view of an optimistic, limitless future. But we don't do justice to that view—how could we, older mammals on the way to extinction that we are? We try. But then we return to fuss, questioning the ascetic dimension of scientists, their romance with black boxes. And argue for a science of many tongues.     

Simulation vs. Understanding: A Tension,in Quantum Chemistry and Beyond. Part A. Stage Setting

We begin our tripartite Essay with a triangle of understanding, theory and simulation. Sketching the intimate tie between explanation and teaching, we also point to the emotional impact of understanding. As we trace the development of theory in chemistry, Dirac's characterization of what is known and what is needed for theoretical chemistry comes up, as does the role of prediction, and Thom's phrase “To predict is not to explain.” We give a typology of models, and then describe, no doubt inadequately, machine learning and neural networks. In the second part, we leave philosophy, beginning by describing Roald's being beaten by simulation. This leads us to artificial intelligence (AI), Searle's Chinese room, and Strevens’ account of what a go‐playing program knows. Back to our terrain—we ask “Quantum Chemistry, ? ca. 2020?” Then move to examples of AI affecting social matters, ranging from trivial to scary. We argue that moral decisions are hardly to be left to a computer. At this point, we try to pull the reader up, giving the opposing view of an optimistic, limitless future a voice. But we don't do justice to that view—how could we? We return to questioning the ascetic dimension of scientists, their romance with black boxes. Onward: In the 3rd part of this Essay, we work our way up from pessimism. We trace (another triangle!) the special interests of experimentalists, who want the theory we love, and reliable numbers as well. We detail in our own science instances where theory gave us real joy. Two more examples‐on magnetic coupling in inorganic diradicals, and the way to think about alkali metal halides, show us the way to integrate simulation with theory. Back and forth is how it should be—between painfully‐obtained, intriguing numbers, begging for interpretation, in turn requiring new concepts, new models, new theoretically grounded tools of computation. Through such iterations understanding is formed. As our tripartite Essay ends, we outline a future of consilience, with a role both for fact‐seekers, and searchers for understanding. Chemistry's streak of creation provides in that conjoined future a passage to art and to perceiving, as we argue we must, the sacred in science.     

Simulation vs. Understanding: A Tension,in Quantum Chemistry and Beyond. Part A. Stage Setting

We begin our tripartite Essay with a triangle of understanding, theory and simulation. Sketching the intimate tie between explanation and teaching, we also point to the emotional impact of understanding. As we trace the development of theory in chemistry, Dirac's characterization of what is known and what is needed for theoretical chemistry comes up, as does the role of prediction, and Thom's phrase “To predict is not to explain.” We give a typology of models, and then describe, no doubt inadequately, machine learning and neural networks. In the second part, we leave philosophy, beginning by describing Roald's being beaten by simulation. This leads us to artificial intelligence (AI), Searle's Chinese room, and Strevens’ account of what a go-playing program knows. Back to our terrain—we ask “Quantum Chemistry, † ca. 2020?” Then move to examples of AI affecting social matters, ranging from trivial to scary. We argue that moral decisions are hardly to be left to a computer. At this point, we try to pull the reader up, giving the opposing view of an optimistic, limitless future a voice. But we don't do justice to that view—how could we? We return to questioning the ascetic dimension of scientists, their romance with black boxes. Onward: In the 3rd part of this Essay, we work our way up from pessimism. We trace (another triangle!) the special interests of experimentalists, who want the theory we love, and reliable numbers as well. We detail in our own science instances where theory gave us real joy. Two more examples-on magnetic coupling in inorganic diradicals, and the way to think about alkali metal halides, show us the way to integrate simulation with theory. Back and forth is how it should be—between painfully-obtained, intriguing numbers, begging for interpretation, in turn requiring new concepts, new models, new theoretically grounded tools of computation. Through such iterations understanding is formed. As our tripartite Essay ends, we outline a future of consilience, with a role both for fact-seekers, and searchers for understanding. Chemistry's streak of creation provides in that conjoined future a passage to art and to perceiving, as we argue we must, the sacred in science.     

Our Future,Our Heritage. The Chemical Family Tree of Tetsuo Nozoe

Note from the Editor: When I was editing Tetsuo Nozoe's autobiography Seventy Years in Organic Chemistry in the late 1980s, I realized that the history of Japanese organic chemistry was not too well known in countries other than Japan. I urged Professor Nozoe to include the historical context of his life in his writings, and I was absolutely delighted that he did so. I also suggested that he publish a “Riko Majima Family Tree in Chemistry.” Majima was not only Nozoe's professor but, as detailed in Nozoe's autobiography and elsewhere in the literature, the father figure of Japanese organic chemistry. Nozoe was reluctant because to single‐out some chemical academics but not others in such a public manner could—would—prove embarrassing. But faithful to his profession, the obligations to history prevailed and Nozoe's autobiography contains the Majima Family Tree. We now skip ahead 25 years where we are immersed in the publication of the Nozoe Autograph Books (see: http://www.tcr.wiley‐vch.de/nozoe and this introductory essay: J. I. Seeman, Chem. Rec. 2012 , 12, 517–531). I find myself once again an editor studying in the life and legacies of Riko Majima and Tetsuo Nozoe. The “repeating experiences” of history have been felt once again! ² I asked Professors Ichiro Murata, Shô Itô, and Toyonobu Asao (who are Professor Nozoe's students and biographers) to follow Professor Nozoe's lead and provide his Family Tree in Chemistry. What follows is a reproduction of the Majima Family Tree as provided by Professor Nozoe along with the next generation Family Tree, that being the students of Tetsuo Nozoe's students who themselves became illustrious professors. —Jeffrey I. Seeman Guest Editor University of Richmond Richmond, Virginia 23173, USA E‐mail: jseeman@richmond.edu     

Simulation vs. Understanding: A Tension,in Quantum Chemistry and Beyond. Part C. Toward Consilience

In the last part of our Essay, we outline a future of consilience, with a role both for fact-seekers, and for searchers for understanding. We begin by looking at theory and simulation, surrounded as they are by and interacting with experiment, especially in Chemistry. Experimenters ask questions both conceptual and numerical, and so draw the communities together. Two case studies show what brings the theoretician authors joy in this playground, and two more detailed ones make it clear that computation/simulation is anyway deeply intertwined with theory-building in what we do, or for that matter, anywhere in the profession. From a definition of science we try to foresee how simulation and theory will interact in the AI-dominated future. We posit that Chemistry's streak of creation provides in that conjoined future a link to Art, and a passage to a renewed vision of the sacred in science.     

Frontispiece: What Are We Missing by Not Measuring the Net Charge of Proteins?

The net electrostatic charge (Z) of a folded protein in solution represents a bird's eye view of its surface potentials—including contributions from tightly bound metal, solvent, buffer, and cosolvent ions—and remains one of its most enigmatic properties. Few tools are available to the average biochemist to rapidly and accurately measure Z at pH≠pI. Tools that have been developed more recently seem to go unnoticed. Most scientists are content with this void and estimate the net charge of a protein from its amino acid sequence, using textbook values of pK_a. Thus, Z remains unmeasured for nearly all folded proteins at pH≠pI. When marveling at all that has been learned from accurately measuring the other fundamental property of a protein—its mass—one wonders: what are we missing by not measuring the net charge of folded, solvated proteins? A few big questions immediately emerge in bioinorganic chemistry. When a single electron is transferred to a metalloprotein, does the net charge of the protein change by approximately one elementary unit of charge or does charge regulation dominate, that is, do the pK_a values of most ionizable residues (or just a few residues) adjust in response to (or in concert with) electron transfer? Would the free energy of charge regulation (ΔΔG_z) account for most of the outer sphere reorganization energy associated with electron transfer? Or would ΔΔG_z contribute more to the redox potential? And what about metal binding itself? When an apo-metalloprotein, bearing minimal net negative charge (e.g., Z=−2.0) binds one or more metal cations, is the net charge abolished or inverted to positive? Or do metalloproteins regulate net charge when coordinating metal ions? The author's group has recently dusted off a relatively obscure tool—the “protein charge ladder”—and used it to begin to answer these basic questions.     

Simulation vs. Understanding: A Tension,in Quantum Chemistry and Beyond. Part C. Toward Consilience

In the last part of our Essay, we outline a future of consilience, with a role both for fact‐seekers, and for searchers for understanding. We begin by looking at theory and simulation, surrounded as they are by and interacting with experiment, especially in Chemistry. Experimenters ask questions both conceptual and numerical, and so draw the communities together. Two case studies show what brings the theoretician authors joy in this playground, and two more detailed ones make it clear that computation/simulation is anyway deeply intertwined with theory‐building in what we do, or for that matter, anywhere in the profession. From a definition of science we try to foresee how simulation and theory will interact in the AI‐dominated future. We posit that Chemistry's streak of creation provides in that conjoined future a link to Art, and a passage to a renewed vision of the sacred in science.     

Berthelot’s Pathway from Synthesis to Thermochemistry

Why did Marcellin Berthelot turn away from his successful research in organic synthesis around 1864 to devote himself to the difficult and uncertain path of thermochemistry? Jean Jacques and others have argued that Berthelot’s shift can be seen as a result of his flawed understanding of the emerging atomistically based theories of structural chemistry; a sense that he was being left behind by this field, it is maintained, led him to try something different. In contrast, I will argue that thermochemistry was a logical progression of Berthelot’s overarching desire to predict chemical action, a great challenge in the middle of the nineteenth century. Berthelot hoped and expected that synthesis and chemical industry would transform the conditions of our existence. He asked such questions as: What substances can we expect to create? From which reagents? And most important: how can we tell in advance whether a particular chemical reaction will occur?     

Pierre Duhem: Mixture and Chemical Combination and Related Essays. Edited and translated, with an Introduction, by Paul Needham

The following is an essay review of Paul Needham's translation of Pierre Duhem's Lemixte et la combinaison chimique and a numberof other essays. In this review we describe theintent and general features of Le mixte and try to place it in the larger context of Duhem'sprogram for energetics. The long essay (Essay3) opposing Marcellin Berthelot'sthermochemistry is singled out for detailedcommentary, since it gives Duhem's reasons forendorsing Josiah Willard Gibbs's chemicalstatics. We argue that a chemical mechanics ofa Gibbsian sort, defended in Le mixte and otheressays in this volume, was the inspiration for,and basis of, Duhem's energetics. Needham'swelcome translations help an English-languageaudience to better understand the basiccontours of Duhem's important, if ultimatelymisguided, project. We conclude with somecomments on the difficulties in translatingDuhem and on the quality of the translationsNeedham has provided. This revised version was published online in July 2006 with corrections to the Cover Date.     

Factors Determining the Selection of Organic Reactions by Medicinal Chemists and the Use of These Reactions in Arrays (Small Focused Libraries)

Synthetic organic reactions are a fundamental enabler of small‐molecule drug discovery, and the vast majority of medicinal chemists are initially trained—either at universities or within industry—as synthetic organic chemists. The sheer breadth of synthetic methodology available to the medicinal chemist represents an almost endless source of innovation. But what reactions do medicinal chemists use in drug discovery? And what criteria do they use in selecting synthetic methodology? Why are arrays (small focused libraries) so powerful in the lead‐optimization process? In this Minireview, we suggest some answers to these questions and also describe how we have tried to expand the number of robust reactions available to the medicinal chemist.     

Broder and Karlin's formula for hitting times and the Kirchhoff Index

We give an elementary proof of an extension of Broder and Karlin's formula for the hitting times of an arbitrary ergodic Markov chain. Using this formula in the particular case of random walks on graphs, we give upper and tight lower bounds for the Kirchhoff index of any N‐ vertex graph in terms of N and its maximal and minimal degrees. We also apply the formula to a closely related index that takes into account the degrees of the vertices between which the effective resistances are computed. We give an upper bound for this alternative index and show that the bound is attained—up to a constant—for the barbell graph. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Effect of Vacancy Defects on the Young's Modulus and Fracture Strength of Graphene: A Molecular Dynamics Study

The Young's modulus of graphene with various rectangular and circular vacancy defects is investigated by molecular dynamics simulation. By comparing with the results calculated from an effective spring model, it is demonstrated that the Young's modulus of graphene is largely correlated to the size of vacancy defects perpendicular to the stretching direction. And a linear reduction of Young's modulus with the increasing concentration of mono‐atomic‐vacancy defects (i.e., the slope of ?0.03) is also observed. The fracture behavior of graphene, including the fracture strength, crack initiation and propagation are then studied by the molecular dynamics simulation, the effective spring model, and the quantized fracture mechanics. The blunting effect of vacancy edges is demonstrated, and the characterized crack tip radius of 4.44 Å is observed.     

Effect of pressure on gas permeability coefficients. A new application of “free volume” theory

The present work is a continuation of a general study of the effect of pressure on gas and vapor permeation through nonporous polymeric membranes. Permeability coefficients have been measured for 1,1-difluoroethylene (C₂H₂F₂) and fluoroform (CHF₃) in polyethylene at penetrant pressures up to 35 atm and at temperatures between -18 and 70°C. The permeability coefficient P? for the 1,1-difluoroethylene—polyethylene system was found to increase with increasing pressure differential Δp across the membrane. Isothermal plots of log ΔP versus Δp are generally linear and can be represented by empirical relations of the form ΔP = P(0)exp{m Δp}, where P(0) and m are constants. The slope m of these isotherms decreases with increasing temperature. Plots of log P? versus Δp for the fluoroform—polyethylene system are also linear, but exhibit negative slopes, i.e., P? decreases with increasing Δp. An extension of Fujita's “free volume” theory of diffusion in polymers shows that the dependence of P? on pressure reflects how the free volume of the polymer is affected by this pressure. An increase in the penetrant pressure may result in two opposing effects: (a) the concentration of the penetrant dissolved in the membrane is increased, thereby increasing the free volume, and (b) the hydrostatic pressure on the membrane is also increased, which causes a decrease in the free volume. If the overall effect is an increase in the free volume of the polymer, then P? will also increase, and vice versa.     

Effects of light and cGMP on membrane fluidity of frog rod outer segments.

Abstract—We have used a spin-labeled fatty acid to detect changes induced by light and by cGMP in isolated rod outer segment membranes. We chose a spin probe (5-doxylstearic acid) which has the nitroxide group placed on the hydrocarbon chain, so the probe should reside somewhat inside the hydrophobic region of the membrane. We found that light exposures which bleached the rhodopsin also produced a small change in the EPR spectra. The spectral changes are consistent with a small increase in membrane fluidity. Light exposures which bleach rhodopsin are known to activate a phosphodiesterase that markedly decreases the cGMP level in rod outer segment. Therefore, we attempted to vary cGMP levels directly by adding Bu₂-cGMP, or indirectly, by adding IBMX, CDTA or ATP to try to inhibit the phosphodiesterase. In each case where the cGMP level is expected to increase, we observed spectral changes in the dark which suggested a small decrease in membrane fluidity. Thus, all of our results with this probe are consistent with the idea that changing the level of cGMP produces changes in membrane fluidity. The light-induced spectral changes we observed required the presence of ATP, and were inhibited by 2mM Ca²⁺, or by the chelator of divalent cations, CDTA.     

From Candles to Cabinets: “Familiar Chemistry” in Early Victorian Britain

Abstract

“Familiar chemistry” flourished in early Victorian Britain. This set of texts an practices advocated drawing scientific lessons from the habitual activities of daily life, in which the hidden chemical contents of common objects and quotidian processes were revealed. Through sensory interactions in the family environment — enlightening conversation and hands-on explorations — a wide range of phenomena could be introduced to childish bodies and minds. A close reading of texts such as Albert J. Bernays' Household Chemistry (1852), alongside a consideration of everyday artefacts, as well as novel specialist objects such as Robert Best Ede's “Youth's Laboratory” (ca. 1837–1845), allows a discussion of this educational style, and an introduction of this new analytic category. In particular, I argue, familiar chemistry succeeded by reworking the popular literary genre of the familiar introduction with an emphasis on embodied interactions with emphatically real things, and gave a central role to the familial domestic context. From candles to cabinets, and beyond, in this article I will demonstrate that familiar chemistry provides a new perspective on scientific education and participation in the nineteenth century.     

Densities of liquid metals: calcium,strontium, barium

Abstract

We report a method of measuring the densities of liquids at intermediate temperatures which employs Archimedes' Principle in a two-sinker arrangement. This method is then used to measure the densities of pure liquid calcium, strontium, and barium. We find ρ(Ca) = 1.4931 ? 1.37 × 10^?4 T(°C) from 850 ? 950°C, ρ(Sr) = 2.5547 ? 2.83 × 10^?4 T(°C) from 780 ? 880°C, and ρ(Ba) = 3.5561 ? 2.99 × 10^?4 T(°C) from 730 ? 830°C, where the units are gm/cm³. We use relations critical constants for these liquids to estimated dρ/dT, and compare these values of dρ/dT with those for other liquid metals; we also compare our results with recent x-ray diffraction data for these liquid metals.     

Reconstitution of Motor Proteins through Molecular Assembly

What is the most favorite and original chemistry developed in your research group?The most favorite and original chemistry developed in my research group is about the reconstitution of motor proteins in artificially designed and assembled units.It is based on the molecular assembly technique,but the method is different from the conventional approach.     

UV Signature Mutations

Sequencing complete tumor genomes and exomes has sparked the cancer field's interest in mutation signatures for identifying the tumor's carcinogen. This review and meta‐analysis discusses signatures and their proper use. We first distinguish between a mutagen's canonical mutations—deviations from a random distribution of base changes to create a pattern typical of that mutagen—and the subset of signature mutations, which are unique to that mutagen and permit inference backward from mutations to mutagen. To verify UV signature mutations, we assembled literature datasets on cells exposed to UVC, UVB, UVA, or solar simulator light (SSL) and tested canonical UV mutation features as criteria for clustering datasets. A confirmed UV signature was: ≥60% of mutations are C→T at a dipyrimidine site, with ≥5% CC→TT. Other canonical features such as a bias for mutations on the nontranscribed strand or at the 3′ pyrimidine had limited application. The most robust classifier combined these features with criteria for the rarity of non‐UV canonical mutations. In addition, several signatures proposed for specific UV wavelengths were limited to specific genes or species; UV's nonsignature mutations may cause melanoma BRAF mutations; and the mutagen for sunlight‐related skin neoplasms may vary between continents.     

Ethylenediamine-Derived Chromatographic Ligand to Separate BSA,Lysozyme, and RNase A

Chromatography has become an essential tool for the purification of proteins, since most purification schemes involve some forms of this methodology. Recently, using chromatographic matrices prepared from symmetrical aminosquarylium cyanine dyes immobilized on Sepharose via a central alkylamino residue, we were able to isolate lysozyme, α-chymotrypsin and trypsin from a mixture. Following this, we envisioned that the immobilization of an asymmetric squarylium dye bearing an N-carboxyethyl group in one of its ending nuclei, on ethylenediamine-activated Sepharose, through EDC/NHS amidation coupling, could enhance the ligand’s mobility and improve the interactions with the target proteins. The prepared support was found to separate an artificial mixture of BSA, lysozyme, and RNase A. Unexpectedly, the support prepared in the absence of the dye exhibited a separation performance similar to that of the dyed support, contrary to that observed in all previous studies using cyanine dyes as ligands for affinity chromatography, which prompted us to try to determine the structural molecular constitution of the matrix surface. A synthetic route to the final chromatographic support could be devised, which is believed to consist in the cyclization of two nearby ethylenediamine units, involving the inclusion of a succinimide-derived residue between them and the EDC-mediated Lossen rearrangement of an intermediary hydroxamic acid.