Background:Humans are exposed to thousands of man-made chemicals in the environment. Some chemicals mimic natural endocrine hormones and, thus, have the potential to be endocrine disruptors. Most of these chemicals have never been tested for their ability to interact with the estrogen receptor (ER). Risk assessors need tools to prioritize chemicals for evaluation in costly in vivo tests, for instance, within the U.S. EPA Endocrine Disruptor Screening Program.Objectives:We describe a large-scale modeling project called CERAPP (Collaborative Estrogen Receptor Activity Prediction Project) and demonstrate the efficacy of using predictive computational models trained on high-throughput screening data to evaluate thousands of chemicals for ER-related activity and prioritize them for further testing.Methods:CERAPP combined multiple models developed in collaboration with 17 groups in the United States and Europe to predict ER activity of a common set of 32,464 chemical structures. Quantitative structure–activity relationship models and docking approaches were employed, mostly using a common training set of 1,677 chemical structures provided by the U.S. EPA, to build a total of 40 categorical and 8 continuous models for binding, agonist, and antagonist ER activity. All predictions were evaluated on a set of 7,522 chemicals curated from the literature. To overcome the limitations of single models, a consensus was built by weighting models on scores based on their evaluated accuracies.Results:Individual model scores ranged from 0.69 to 0.85, showing high prediction reliabilities. Out of the 32,464 chemicals, the consensus model predicted 4,001 chemicals (12.3%) as high priority actives and 6,742 potential actives (20.8%) to be considered for further testing.Conclusion:This project demonstrated the possibility to screen large libraries of chemicals using a consensus of different in silico approaches. This concept will be applied in future projects related to other end points.Citation:Mansouri K, Abdelaziz A, Rybacka A, Roncaglioni A, Tropsha A, Varnek A, Zakharov A, Worth A, Richard AM, Grulke CM, Trisciuzzi D, Fourches D, Horvath D, Benfenati E, Muratov E, Wedebye EB, Grisoni F, Mangiatordi GF, Incisivo GM, Hong H, Ng HW, Tetko IV, Balabin I, Kancherla J, Shen J, Burton J, Nicklaus M, Cassotti M, Nikolov NG, Nicolotti O, Andersson PL, Zang Q, Politi R, Beger RD, Todeschini R, Huang R, Farag S, Rosenberg SA, Slavov S, Hu X, Judson RS. 2016. CERAPP: Collaborative Estrogen Receptor Activity Prediction Project. Environ Health Perspect 124:1023–1033; http://dx.doi.org/10.1289/ehp.1510267

Marcus theory has explained how thermal nuclear motions modulate the energy gap between donor and acceptor sites in protein electron transfer reactions. Thermal motions, however, may also modulate electron tunneling between these reactions. Here we identify a new mechanism of nuclear dynamics amplification that plays a central role when interference among the dominant tunneling pathway tubes is destructive. In these cases, tunneling takes place in protein conformations far from equilibrium that minimize destructive interference. As an example, we demonstrate how this dynamical amplification mechanism affects certain reaction rates in the photosynthetic reaction center and therefore may be critical for biological function.

Structured water molecules near redox cofactors were found recently to accelerate electrontransfer (ET) kinetics in several systems. Theoretical study of interprotein electron transfer across an aqueous interface reveals three distinctive electronic coupling mechanisms that we describe here: (i) a protein-mediated regime when the two proteins are in van der Waals contact; (ii) a structured water-mediated regime featuring anomalously weak distance decay at relatively close protein-protein contact distances; and (iii) a bulk water-mediated regime at large distances. Our analysis explains a range of otherwise puzzling biological ET kinetic data and provides a framework for including explicit water-mediated tunneling effects on ET kinetics.Protein ET reactions play a critical role in biologically vital processes in living cells, most notably photosynthesis and respiration (1). Describing the structure dependence of intermolecular ET reactions is particularly challenging because of the wide range of the accessible docking geometries, and several studies have addressed these reaction mechanisms (2-8). The factors that control unimolecular ET rates, namely the donor-toacceptor (D to A) distance and energies, the structure of the ET-mediating protein matrix, and the thermal atomic motion, have been extensively explored both experimentally (4-6) and theoretically (9-14).Intermolecular ET reactions, however, remain a challenge. In addition to the above factors, the rate depends on the D-to-A docking geometry, as well as on the structure and thermal motion of the solvent (2-7). The number of structural degrees of freedom makes quantitatively reliable theoretical calculations extremely difficult. We show that the intervening water structure leads to one of three distinctly different ET tunneling regimes, in contrast to the common assumption of single-exponential distance decay (2, 5-7). The identification of these three regimes provides a framework for understanding the mechanisms that underlie several unexplained and seemingly unrelated water-mediated biological ET rate processes (7,(15)(16)(17)(18)(19), as well as providing a strategy for making theoretical estimates of bimolecular rates that take these water-mediation effects into account.Water can influence the ET reaction rates by mediating ET coupling pathways, as well as by controlling activation free energies (5, 9). In the past decade, the distance dependence of water-mediated ET reaction rates has become the focus of intensive experimental (4-7, 13, * To whom correspondence should be addressed: david.beratan@duke.edu. 15-17, 20, 21) and theoretical (18, 19, 22-24) investigation. Until recently, experimental and theoretical analysis suggested a single-exponential decay of the ET rates with distance through water, with a characteristic decay constant of about 1.6 to 1.7 Å −1 (5,20,21). In comparison with proteins that exhibit decay constants of about 1.0 to 1.2 Å −1 (5), water appeared to be a rather poor ET mediator because of extensive through-space link...

ConspectusElectron transfer (ET) reactions provide a nexus among chemistry, biochemistry, and physics. These reactions underpin the "power plants" and "power grids" of bioenergetics, and they challenge us to understand how evolution manipulates structure to control ET kinetics. Ball-and-stick models for the machinery of electron transfer, however, fail to capture the rich electronic and nuclear dynamics of ET molecules: these static representations disguise, for example, the range of thermally accessible molecular conformations. The influence of structural fluctuations on electron-transfer kinetics is amplified by the exponential decay of electron tunneling probabilities with distance, as well as the delicate interference among coupling pathways. Fluctuations in the surrounding medium can also switch transport between coherent and incoherent ET mechanisms-and may gate ET so that its kinetics is limited by conformational interconversion times, rather than by the intrinsic ET time scale. Moreover, preparation of a charge-polarized donor state, or of a donor state with linear or angular momentum, can have profound dynamical and kinetic consequences. In this Account, we establish a vocabulary to describe how the conformational ensemble and the prepared donor state influence ET kinetics in macromolecules. This framework is helping to unravel the richness of functional biological ET pathways, which have evolved in within fluctuating macromolecular structures.The conceptual framework for describing nonadiabatic ET seems disarmingly simple: compute the ensemble averaged (mean-squared) donor-acceptor (DA) tunneling interaction, , and the Franck-Condon weighted density of states, ρ FC , to describe the rate: (2π/ħ) ρ FC . Modern descriptions of the thermally averaged electronic coupling and of the Franck-Condon factor establish a useful predictive framework in biology, chemistry, and nanoscience. Describing the influence of geometric and energetic fluctuations on ET allows us to address a rich array of mechanistic and kinetic puzzles. How strongly is a protein's fold imprinted on the ET kinetics, and might thermal fluctuations "wash out" signatures of structure? What is the influence of thermal fluctuations on ET kinetics beyond averaging of the tunneling barrier structure? Do electronic coupling mechanisms change as donor and acceptor reposition in a protein, and what are the consequences for the ET kinetics? Do fluctuations access minority species that dominate tunneling? Can energy exchanges between the electron and bridge vibrations generate vibronic signatures that label some of the D-to-A pathway traversed by the electron, thus eliminating unmarked pathways that would otherwise contribute to the DA coupling (as in other "which way" or double-slit experiments)? Might medium fluctuations drive tunneling-hopping mechanistic transitions? How does the donor-state preparation -in particular its polarization toward the acceptor and its momentum characteristics (which may introduce complex rather than pur...

We compute the autocorrelation function of the donor-acceptor tunneling matrix element ͗TDA(t)TDA ( (0)͘ is studied as a function of donor-acceptor distance, tunneling pathway structure, tunneling energy, and temperature to explore the structural and dynamical origins of non-Condon effects. For azurin, the correlation function is remarkably insensitive to tunneling pathway structure. The decay time is only slightly shorter than it is for solvent-mediated electron transfer in small organic molecules and originates, largely, from fluctuations of valence angles rather than bond lengths.correlation functions ͉ Franck-Condon breakdown ͉ dephasing ͉ coupling pathways ͉ redox reactions T he interplay among nuclear motion and electronic dynamics is the subject of increasing focus in the field of electron transfer (ET) processes (1-8). Recent research has focused on the effects of bridge nuclear motion on ET, with chemical, biological, and electronic device applications (see refs. 9-11 for reviews). Early theoretical analysis indicates that tunneling matrix element modulation by bridge dynamics can alter the free energy dependence of ET reaction rates by causing the Born-Oppenheimer (12) and FranckCondon approximations to fail (13-15). More recently, theoretical studies explored ET kinetics in systems with fluctuating donoracceptor matrix elements (16-24). Bridge motion can cause large and rapid donor-acceptor matrix element fluctuations, affecting the tunneling pathway structure and the interferences among pathways (25-37). The coupling matrix element fluctuations may have large contributions from solvent-polarization fluctuations (23), and these fluctuations facilitate electronically forbidden and gated . Finally, bridge-nuclear relaxation creates inelastic tunneling pathway channels (11,20,24,(47)(48)(49) that can change the mechanism of ET from superexchange to resonant tunneling to sequential hopping (11,(41)(42)(43)(44)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62) and can lead to breakdown of the Born-Oppenheimer approximation (63, 64).The goal of this work is to characterize tunneling matrix element fluctuations in azurin and, in particular, to examine their influence on the ET rate and on the validity of the Franck-Condon approximation. Franck-Condon breakdown can reduce the ET rate in the case of activationless ET reactions and enhance the rate for activated ET (18). ET in Ru-modified azurin is nearly activationless, and the protein is often approximated as being a rigid medium for tunneling because the tunneling pathways traverse a ␤ sheet. In this work, we compute the effects of tunneling matrix element fluctuations on the rate as a function of distance, temperature, protein structural fluctuations, and intervening pathway structure. Further, we identify the types of motion that cause the coupling to fluctuate.The general derivation of the nonadiabatic rate expression for fluctuating donor-acceptor matrix elements cannot assume the validity of the Franck-Condon separation. As explained below, the Franck...

F(1)F(o)-ATP synthase is a ubiquitous membrane protein complex that efficiently converts a cell's transmembrane proton gradient into chemical energy stored as ATP. The protein is made of two molecular motors, F(o) and F(1), which are coupled by a central stalk. The membrane unit, F(o), converts the transmembrane electrochemical potential into mechanical rotation of a rotor in F(o) and the physically connected central stalk. Based on available data of individual components, we have built an all-atom model of F(o) and investigated through molecular dynamics simulations and mathematical modeling the mechanism of torque generation in F(o). The mechanism that emerged generates the torque at the interface of the a- and c-subunits of F(o) through side groups aSer-206, aArg-210, and aAsn-214 of the a-subunit and side groups cAsp-61 of the c-subunits. The mechanism couples protonation/deprotonation of two cAsp-61 side groups, juxtaposed to the a-subunit at any moment in time, to rotations of individual c-subunit helices as well as rotation of the entire c-subunit. The aArg-210 side group orients the cAsp-61 side groups and, thereby, establishes proton transfer via aSer-206 and aAsn-214 to proton half-channels, while preventing direct proton transfer between the half-channels. A mathematical model proves the feasibility of torque generation by the stated mechanism against loads typical during ATP synthesis; the essential model characteristics, e.g., helix and subunit rotation and associated friction constants, have been tested and furnished by steered molecular dynamics simulations.

We describe the new Pathways plugin for the molecular visualization program VMD. The plugin identifies and visualizes tunneling pathways and pathway families in biomolecules and calculates relative electronic couplings. The plugin includes unique features to estimate the importance of individual atoms for mediating the coupling, to analyze the coupling sensitivity to thermal motion, and to visualize pathway fluctuations. The Pathways plugin is open source software distributed under the terms of the GNU public license.

BACKGROUND: Endocrine disrupting chemicals (EDCs) are xenobiotics that mimic the interaction of natural hormones and alter synthesis, transport, or metabolic pathways. The prospect of EDCs causing adverse health effects in humans and wildlife has led to the development of scientific and regulatory approaches for evaluating bioactivity. This need is being addressed using high-throughput screening (HTS) in vitro approaches and computational modeling. OBJECTIVES: In support of the Endocrine Disruptor Screening Program, the U.S. Environmental Protection Agency (EPA) led two worldwide consortiums to virtually screen chemicals for their potential estrogenic and androgenic activities. Here, we describe the Collaborative Modeling Project for Androgen Receptor Activity (CoMPARA) efforts, which follows the steps of the Collaborative Estrogen Receptor Activity Prediction Project (CERAPP).