Can the calculation of ligand binding free energies be improved with continuum solvent electrostatics and an ideal-gas entropy correction?
The prediction of a ligand binding constant requires generating three-dimensional structures of the complex concerned and reliably scoring these structures. Here, the scoring problem is investigated by examining benzamidine-like inhibitors of trypsin, a system for which errors in the structures are small. Precise and consistent binding free energies for the inhibitors are determined experimentally for this test system. To examine possible improvement of scoring methods, we test the suitability of continuum electrostatics to account for solvation effects and use an ideal-gas entropy correction to account for the changes in the degrees of freedom of the ligand. The small observed root-mean-square deviation of 0.55 kcal/mol of the calculated relative to the experimental values indicates that the essentials of the binding process have been captured. Even though all six ligands make the same salt bridge and H-bonds to the protein, the electrostatic contribution varies among the ligands by as much as 2 kcal/mol. Moreover, although the ligands are rigid and similar in size, the entropic terms also significantly affect the relative binding affinities (by up to 2.7 kcal/mol). The present approach to solvation and entropy may allow the ranking of the ligands to be considerably improved at a cost that makes the method applicable to the optimization of lead compounds or to the screening of small collections of ligands.

title: Docking by Monte Carlo minimization with a solvation correction: Application to an FKBP - substrate complex
abstract: A Monte Carlo docking procedure that combines random displacements of the substrate and protein side chains with minimization of the enzyme]substrate complex is described and applied to finding the binding mode of the blocked tetrapeptide N-acetyl-Leu-Pro-Phe-methylamide to the FK506 binding protein Ž .  The tetrapeptide, an analog of the preferred FKBP substrate, and the FKBP binding site are flexible during the docking procedure. The twisted-imide transition-state form of the substrate is used during docking. The enzyme charges are scaled individually to account for solvent screening of specific binding site residues during the Monte Carlo sampling. To evaluate the relative binding free energies of the resulting structures, a rapid method for calculating polar and nonpolar solvation effects is introduced. Accurate electrostatic solute]solvent energies are calculated by solving the finite-difference linearized Poisson]Boltzmann equation; nonpolar contributions to the stability of the different conformers are estimated by the free energy of cavity formation, which is obtained from the molecular surface, and the solute]solvent van der Waals energy, which is calculated with a continuum approach. In the conformation of the enzyme]substrate complex with the lowest free energy, the tetrapeptide is bound as a type VIa proline turn with solvent accessible ends to permit longer polypeptide chains to act as substrates. Except for the imide carbonyl, which is involved in polar interactions with aromatic side chains of the FKBP binding *Present address: Pharmaceutical Research, F. Hoffmann]La Roche Ltd., CH-4070 Basel, Switzerland. Author to whom all correspondence should be addressed. ( 21 CAFLISCH, FISCHER, AND KARPLUS site, all of the seven potential hydrogen bond donors or acceptors of the tetrapeptide are satisfied. The FKBP binding site has a similar conformation in the substrate complex as in the FKBP-FK506 cocrystal structure, except for the predicted reorientation of the Tyr 82 hydroxyl, which plays an important role in substrate binding. The present model for the FKBP]substrate complex is in agreement with the recently determined crystal structure of a cyclic peptide]FK506 hybrid bound to FKBP and supports the structure obtained previously by iterative model building. In addition, it is consistent with the observed effects of FKBP point mutations on the enzyme activity. The approach described here should be useful, in general, for the prediction of the structure of a molecule in solution or as part of a complex. It provides for the effective sampling of conformational space and for the inclusion of solvent effects. Q 1997 by John Wiley & Sons, Inc.

title: How well does charge reparametrisation account for solvent screening in molecular mechanics calculations? The example of myosin
abstract: The rate constant of an enzyme-catalysed reaction is one of the major target properties to understand protein function. Atomic-detail computer simulations can in principle be used to estimate rate constants from the energy profile along the reaction coordinate. For such simulations, molecular mechanics is combined with a quantum description of the reaction process. In molecular mechanics calculations, the electrostatic field is represented by the Coulomb potential of partial atomic charges which have been parametrised for small building blocks in vacuum and transferred to the macromolecule. In aqueous solution, however, the electrostatic interactions are affected by the solvent polarization. While this can be described by numerically solving the Poisson-Boltzmann equation, it is computationally expensive. A simple approximation to this is to optimally reproduce the electrostatic potential in solution by reparametrising the partial atomic charges in such a way that a simple Coulomb potential can still be used. Such a procedure would allow to perform fast calculations of reaction processes in proteins while accounting for the solvent screening effect. Here, this method is tested on myosin, a motor protein that is both an enzyme and exists in very different conformations.

title: New Features of Latin Dances: Analysis of Salsa, ChaCha, and Rumba
abstract: The stream cipher Salsa20 was introduced by Bernstein in 2005 as a candidate in the eSTREAM project, accompanied by the reduced versions Salsa20/8 and Salsa20/12. ChaCha is a variant of Salsa20 aiming at bringing better diffusion for similar performance. Variants of Salsa20 with up to 7 rounds (instead of 20) have been broken by differential cryptanalysis, while ChaCha has not been analyzed yet. We introduce a novel method for differential cryptanalysis of Salsa20 and ChaCha, inspired by correlation attacks and related to the notion of neutral bits. This is the first application of neutral bits in stream cipher cryptanalysis. It allows us to break the 256-bit version of Salsa20/8, to bring faster attacks on the 7-round variant, and to break 6- and 7-round ChaCha. In a second part, we analyze the compression function Rumba, built as the XOR of four Salsa20 instances and returning a 512-bit output. We find collision and preimage attacks for two simplified variants, then we discuss differential attacks on the original version, and exploit a high-probability differential to reduce complexity of collision search from 2256to 279for 3-round Rumba. To prove the correctness of our approach we provide examples of collisions and near-collisions on simplified versions.

title: The COSIMA prototype for multi-objective bargaining
abstract: Multi-objective bargaining is a challenging business model for B2C or B2B Internet applications. Our visual bargaining agent COSIMA builds on cooperative database technology like Preference SQL or Preference XPATH, which can efficiently implement \linebreak[4] multi-dimensional search engines with a Pareto-optimality semantics to find best alternative offers. COSIMA is a smart avatar with dynamically generated speech output. We have implemented several well-known bargaining strategies for a sample e-shop, where the customer can bargain on more attributes than just the price. The life-like appearance of COSIMA is supported by randomizing her bargaining tactics and by expressing visual emotions during bargaining. She can also learn and adapt dynamically to various bargaining preferences of the customers. The COSIMA prototype is carefully engineered by means of component-ware and IT-standards including SQL, XML and Java. This makes it scalable even to very large e-shop databases. Measurements show that this advanced user interface of COSIMA requires only a small overhead of a few seconds, including the bidding process. Thus real-time performance using state-of-the art software components and hardware is feasible. A preliminary user feedback has been very encouraging. COSIMA gave her debut to a large professional audience at the computer fair CeBIT 2002.

title: Person Authentication by Fusing Face and Speech Information
abstract: vision Reference EPFL-CONF-82406 Record created on 2006-03-10, modified on 2017-05-10

title: COSIMA- your smart, speaking E-salesperson
abstract: We present a new cooperative user interface for e-shopping. COSIMA is an intelligent Internet avatar with dynamic voice output that assists customers through their e-shopping tours and advises them like a real salesperson. COSIMA uses a meta search engine based on Preference SQL, computing best matching results to the customer's wishes. COSIMA can qualify these results and generates proper voice output. Our presentation shows COSIMA in action for comparison shopping.

title: Evaluation and optimization of the catalog search process of e-procurement platforms
abstract: With the emerging of e-catalog standards the product search can be used in a very different and improved matter. Beyond the usual keyword search this opens the arena for attribute-based search engines, including parametric search and preference search. We analyze the impact of different search techniques for such e-catalogs on the overall search process costs. It turns out that preference search has a high potential to significantly reduce the process costs. A large-scale use case with the MAN2B e-procurement platform supports our claim. We identify improvements achievable by using preference search, in particular less navigation steps during the product search and better search results due to the BMO query model. Expensive cases, where frustrated users accept bad search results or phone up the company's purchasing department, should decrease significantly. This in turn will enable the purchasing department to focus more on strategic issues like supplier relationship management than on operative issues as it still happens widely today.