A molecular mechanics/grid method for evaluation of ligand–receptor interactions

We present a computational method for prediction of the conformation of a ligand when bound to a macromolecular receptor. The method is intended for use in systems in which the approximate location of the binding site is known and no large-scale rearrangements of the receptor are expected upon formation of the complex. The ligand is initially placed in the vicinity of the binding site and the atomic motions of the ligand and binding site are explicitly simulated, with solvent represented by an implicit solvation model and using a grid representation for the bulk of the receptor protein. These two approximations make the method computationally efficient and yet maintain accuracy close to that of an all-atom calculation. For the benzamidine/trypsin system, we ran 100 independent simulations, in many of which the ligand settled into the low-energy conformation observed in the crystal structure of the complex. The energy of these conformations was lower than and well-separated from that of others sampled. Extensions of this method are also discussed. © 1995 by John Wiley & Sons, Inc.     

The Rôle of Solvent Participation in Electrophilic Aromatic Substitution: Rates of a diazo coupling reaction in water and in aprotic polar solvents. 24th Communication on diazo coupling reactions

The rates of the diazo coupling reaction of 4-toluenediazonium salts with N, N-dimethylaniline in tetramethylene sulfone, acetonitrile, water, and nitromethane at 30°C are the same within a factor of 5. No significant influence of ‘gegenions’ (HSO or BF) was found. The results are explained by postulating little solvent reorganisation in the transition state. They are discussed comparatively with solvent effects in other electrophilic aromatic substitutions, particularly with regard to the reactions of nitronium salts.     

Stability and bonding of disilyne and its isomers: A generalized valence bond-effective potential study

We have employed an effective potential and a single-zeta basis in SCF–MO computations to estimate the relative stability of linear disilyne HSiSiH and five isomeric structures defined in earlier all-electron ab initio SCF–MO computations. The effect of electron correlation has been estimated by generalized valence-bond (GVB ) computations for the five valence electron pairs of these structures. All our computations indicate that linear disilyne is the least stable structure and that H₂SiSi, the silicon analog of vinylidene carbene, is the most stable structure. In these structures silicon occurs in divalent and tetravalent states. The nature of silicon bonding in these valence states is illustrated by contour diagrams of the GVB orbital pairs.     

Meta-control of an interacting-particle algorithm for global optimization

A common issue for stochastic global optimization algorithms is how to set the parameters of the sampling distribution (e.g. temperature, mutation/cross-over rates, selection rate, etc.) so that the samplings converge to the optimum effectively and efficiently. We consider an interacting-particle algorithm and develop a meta-control methodology which analytically guides the inverse temperature parameter of the algorithm to achieve desired performance characteristics (e.g. quality of the final outcome, algorithm running time, etc.). The main aspect of our meta-control methodology is to formulate an optimal control problem where the fractional change in the inverse temperature parameter is the control variable. The objectives of the optimal control problem are set according to the desired behavior of the interacting-particle algorithm. The control problem considers particles’ average behavior, rather than treating the behavior of individual particles. The solution to the control problem provides feedback on the inverse temperature parameter of the algorithm.     

Optimization of Algorithmic Parameters using a Meta-Control Approach*

Optimization algorithms usually rely on the setting of parameters, such as barrier coefficients. We have developed a generic meta-control procedure to optimize the behavior of given iterative optimization algorithms. In this procedure, an optimal continuous control problem is defined to compute the parameters of an iterative algorithm as control variables to achieve a desired behavior of the algorithm (e.g., convergence time, memory resources, and quality of solution). The procedure is illustrated with an interior point algorithm to control barrier coefficients for constrained nonlinear optimization. Three numerical examples are included to demonstrate the enhanced performance of this method. This work was primarily done when Z. Zabinsky was visiting Clearsight Systems Inc.     

Molecular SCF calculations to model (III) surface relaxation of silicon

Ab-initio SCF-MO computations in a 4–31 Gaussian basis on a molecular system Si₄H₉, designed to model a silicon atom on the (III) surface of silicon, predict that the dangling bound silicon relaxes about 0.05 Å toward the bulk from its position on an extension of the silicon crystal lattice. This relaxation is much less than earlier empirical estimates.     

Modulation of αVβ6 integrin in osteoarthritis-related synovitis and the interaction with VTN(381–397 a.a.) competing for TGF-β1 activation

Osteoarthritis is characterized by structural alteration of joints. Fibrosis of the synovial tissue is often detected and considered one of the main causes of joint stiffness and pain. In our earlier proteomic study, increased levels of vitronectin (VTN) fragment (amino acids 381–397) were observed in the serum of osteoarthritis patients. In this work, the affinity of this fragment for integrins and its putative role in TGF-β1 activation were investigated. A competition study determined the interaction of VTN_{(381–397 a.a.)} with α_Vβ₆ integrin. Subsequently, the presence of α_Vβ₆ integrin was substantiated on primary human fibroblast-like synoviocytes (FLSs) by western blot and flow cytometry. By immunohistochemistry, β₆ was detected in synovial membranes, and its expression showed a correlation with tissue fibrosis. Moreover, β₆ expression was increased under TGF-β1 stimulation; hence, a TGF-β bioassay was applied. We observed that α_Vβ₆ could mediate TGF-β1 bioavailability and that VTN_{(381–397 a.a.)} could prevent TGF-β1 activation by interacting with α_Vβ₆ in human FLSs and increased α-SMA. Finally, we analyzed serum samples from healthy controls and patients with osteoarthritis and other rheumatic diseases by nano-LC/Chip MS–MS, confirming the increased expression of VTN_{(381–397 a.a.)} in osteoarthritis as well as in lupus erythematosus and systemic sclerosis. These findings corroborate our previous observations concerning the overexpression of VTN_{(381–397 a.a.)} in osteoarthritis but also in other rheumatic diseases. This fragment interacts with α_Vβ₆ integrin, a receptor whose expression is increased in FLSs from the osteoarthritic synovial membrane and that can mediate the activation of the TGF-β1 precursor in human FLSs.Subject terms: Osteoarthritis, Cell culture     

A meta-control algorithm for generating approximate solutions to binary integer programming problems

Binary integer program problems, which are known to be difficult to solve, have long been an important research area. We use a new approach with continualization techniques to find approximate solutions to binary integer programming problems. The algorithm constructs a sequence of approximations to a solution using a meta-control approach that has low polynomial time complexity. The algorithm is illustrated with a BIP example.     

Phase control of a nano-structured light-harvesting architecture

Efficient solar-energy harvesting is fundamental to solar cell technology. Much research effort has been devoted to the construction of new light-harvesting structures, including the use of semiconductor quantum dots (QDs), to improve the widespread availability of solar cells. In this research, a new light-harvesting architecture is developed, which utilizes quantum dots. The proposed architecture is composed of quantum phase-locked loops (QPLLs) to enhance the harvesting efficiency of QD solar cells by utilizing feedback control principles. The purpose of QPLL is to synchronize the phases of monochromatic light harvested by the antenna systems. This paper addresses deterministic modeling and control formulation of the QPLL within our conceptual framework. The QPLL consists of a tracking controller and a proportional–integral (PI) regulator. The QPLLs are simulated with external fluctuations to evaluate the performance of the controllers. Simulation results show that the tracking controller achieves robust and satisfactory performance. The PI regulator is more sensitive to external fluctuations and the nominal operating point. Our results demonstrate the possibility of improving light-harvesting efficiency by utilizing feedback control principles.