@article{4017, abstract = {Identification and size characterization of surface pockets and occluded cavities are initial steps in protein structure-based ligand design. A new program, CAST, for automatically locating and measuring protein pockets and cavities, is based on precise computational geometry methods, including alpha shape and discrete flow theory. CAST identifies and measures pockets and pocket mouth openings, as well as cavities. The program specifies the atoms lining pockets, pocket openings. and buried cavities; the volume and area of pockets and cavities; and the area and circumference of mouth openings. CAST analysis of over 100 proteins has been carried out; proteins examined include a set of 51 monomeric enzyme-ligand structures, several elastase-inhibitor complexes, the FK506 binding protein, 30 HIV-1 protease-inhibitor complexes, and a number of small and large protein inhibitors, Medium-sized globular proteins typically have 10-20 pockets/cavities. Most often, binding sites are pockets with 1-2 mouth openings; much less frequently they are cavities. Ligand binding pockets vary widely in size, most within the range 10(2)-10(3) Angstrom(3). Statistical analysis reveals that the number of pockets and cavities is correlated with protein size, but there is no correlation between the size of the protein and the size of binding sites. Most frequently, the largest pocket/cavity is thp active site, but there are a number of instructive exceptions. Ligand volume and binding site volume are somewhat correlated when binding site volume is less than or equal to 700 Angstrom(3), but the ligand seldom occupies the entire site. Auxiliary pockets near the active site have been suggested as additional binding surface for designed ligands (Mattos C ct al., 1993, Nat Struct Biol 1:55-58). Analysis of elastase-inhibitor complexes suggests that CAST can identify ancillary pockets, suitable for recruitment in ligand design strategies. Analysis of the FK506 binding protein, and of compounds developed in SAR by NMR (Shuker SE et al.. 1996, Science 274:1531-1534), indicates that CAST pocket computation may provide a priori identification of target proteins for Linked-fragment design. CAST analysis of 30 HIV-1 protease-inhibitor complexes shows that the flexible active site pocket can vary over a range of 853-1,566 Angstrom(3), and that there are two pockets near or adjoining the active site that may be recruited for ligand design.}, author = {Liang, Jie and Edelsbrunner, Herbert and Woodward, Clare}, issn = {0961-8368}, journal = {Protein Science}, number = {9}, pages = {1884 -- 1897}, publisher = {Wiley-Blackwell}, title = {{Anatomy of protein pockets and cavities: Measurement of binding site geometry and implications for ligand design}}, doi = {10.1002/pro.5560070905}, volume = {7}, year = {1998}, } @inproceedings{4019, abstract = {The construction of shape spaces is studied from a mathematical and a computational viewpoint. A program is outlined reducing the problem to four tasks: the representation of geometry, the canonical deformation of geometry, the measuring of distance in shape space, and the selection of base shapes. The technical part of this paper focuses on the second task: the specification of a deformation mixing two or more shapes in continuously, changing proportions.}, author = {Cheng, Ho and Edelsbrunner, Herbert and Fu, Ping}, booktitle = {Proceedings of the 6th Pacific Conference on Computer Graphics and Applications}, isbn = {0818686200}, location = {Singapore}, pages = {104 -- 113}, publisher = {IEEE}, title = {{Shape space from deformation}}, doi = {10.1109/PCCGA.1998.732056}, year = {1998}, } @inbook{4020, abstract = {Space Filing diagrams are geometric models of molecular conformations in three-dimensional space. Each atom is a location is space and a quantitative expression of influence on the immediate surrounding. This paper surveys the basic types of space filling diagrams with a focus on the dual alpha shape. Properties of those diagrams that relate to questions of connectivity, size, shape and symmetry, and metamorphosis are discussed.}, author = {Edelsbrunner, Herbert}, booktitle = {Robotics: The Algorithmic Perspective}, isbn = {9781568810812}, pages = {265 -- 277}, publisher = {AK Peters}, title = {{Geometry for modeling biomolecules}}, year = {1998}, } @article{4280, author = {Ritchie, Mike and Barton, Nicholas H}, issn = {0169-5347}, journal = {Trends in Ecology and Evolution}, number = {7}, pages = {282 -- 283}, publisher = {Cell Press}, title = {{Hybrids and hybrid zones: Reply from M.G. Ritchie and N.H. Barton}}, doi = {10.1016/S0169-5347(98)01396-2}, volume = {13}, year = {1998}, } @article{4281, abstract = {Most higher organisms reproduce sexually, despite the automatic reproductive advantage experienced by asexual variants. This implies the operation of selective forces that confer an advantage to sexuality and genetic recombination, at either the population or individual level. The effect of sex and recombination in breaking down negative correlations between favorable variants at different genetic loci, which increases the efficiency of natural selection, is likely to be a major factor favoring their evolution and maintenance. Various processes that can cause such an effect have been studied theoretically. It has, however, so far proved hard to discriminate among them empirically. }, author = {Barton, Nicholas H and Charlesworth, Brian}, issn = {0036-8075}, journal = {Science}, number = {5385}, pages = {1986 -- 1990}, publisher = {American Association for the Advancement of Science}, title = {{Why sex and recombination?}}, doi = {10.1126/science.281.5385.1986}, volume = {281}, year = {1998}, } @misc{4282, author = {Barton, Nicholas H}, booktitle = {Genetical Research}, issn = {0016-6723}, number = {1}, pages = {73 -- 73}, publisher = {Cambridge University Press}, title = {{Genetics and analysis of quantitative traits}}, doi = {10.1017/S0016672398219732}, volume = {72}, year = {1998}, } @misc{4283, author = {Barton, Nicholas H}, booktitle = {Nature}, issn = {0028-0836}, number = {6704}, pages = {751 -- 752}, publisher = {Nature Publishing Group}, title = {{The geometry of adaptation}}, doi = {10.1038/27338}, volume = {395}, year = {1998}, } @inproceedings{4408, abstract = {This paper presents a complete axiomatization of fully decidable propositional real-time linear temporal logics with past: the Event Clock Logic (ECL) and the Metric Interval Temporal Logic with past (MITL). The completeness proof consists of an effective proof building procedure for ECL. From this result we obtain a complete axiomatization of MITL by providing axioms translating MITL formulae into ECL formulae, the two logics being equally expressive. Our proof is structured to yield a similar axiomatization and procedure for interesting fragments of these logics, such as the linear temporal logic of the real numbers (LTR).}, author = {Raskin, Jean and Schobbens, Pierre and Henzinger, Thomas A}, booktitle = {Proceedings of the 9th Interantional Conference on Concurrency Theory}, isbn = {9783540648963}, location = {Nice, France}, pages = {219 -- 236}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{Axioms for real-time logics}}, doi = {10.1007/BFb0055625}, volume = {1466}, year = {1998}, } @inproceedings{4410, abstract = {Rectangular automata are well suited for approximate modeling of continuous-discrete systems. The exact analysis of these automata is feasible for small examples but can encounter severe numerical problems for even medium-sized systems. This paper presents an analysis algorithm that uses conservative overapproximation to avoid these numerical problems. The algorithm is demonstrated on a simple benchmark system consisting of two connected tanks. Supported by the German Research Council (DFG) under grant Ko1430/3 in the special program KONDISK (‘Continuous-discrete dynamics of technical systems’).}, author = {Preußig, Jörg and Kowalewski, Stefan and Wong Toi, Howard and Henzinger, Thomas A}, booktitle = {Proceedings of the 5th International Symposium on Formal Techniques in Real-Time and Fault-Tolerant Systems}, isbn = {9783540650034}, location = {Lyngby, Denmark}, pages = {228 -- 240}, publisher = {Springer}, title = {{An algorithm for the approximative analysis of rectangular automata}}, doi = {10.1007/BFb0055350}, volume = {1486}, year = {1998}, } @inproceedings{4429, abstract = {We study the reachability problem for hybrid automata. Automatic approaches, which attempt to construct the reachable region by symbolic execution, often do not terminate. In these cases, we require the user to guess the reachable region, and we use a theorem prover (Pvs) to verify the guess. We classify hybrid automata according to the theory in which their reachable region can be defined finitely. This is the theory in which the prover needs to operate in order to verify the guess. The approach is interesting, because an appropriate guess can often be deduced by extrapolating from the first few steps of symbolic execution.}, author = {Henzinger, Thomas A and Rusu, Vlad}, booktitle = {Proceedings of the 1st International Workshop on Hybrid Systems: Computation and Control}, isbn = {9783540643586}, location = {Berkely, CA, United States of America}, pages = {190 -- 204}, publisher = {Springer}, title = {{Reachability verification for hybrid automata}}, doi = {10.1007/3-540-64358-3_40}, volume = {1386}, year = {1998}, } @proceedings{4430, editor = {Henzinger, Thomas A}, isbn = {978-3-540-64358-6}, location = {Berkeley, CA, United States of America}, publisher = {Springer}, title = {{HSCC: Hybrid Systems—Computation and Control}}, doi = {10.1007/3-540-64358-3}, volume = {1386}, year = {1998}, } @inproceedings{4486, abstract = {The simulation preorder on state transition systems is widely accepted as a useful notion of refinement, both in its own right and as an efficiently checkable sufficient condition for trace containment. For composite systems, due to the exponential explosion of the state space, there is a need for decomposing a simulation check of the form P< s Q into simpler simulation checks on the components of P and Q. We present an assume-guarantee rule that enables such a decomposition. To the best of our knowledge, this is the first assume-guarantee rule that applies to a refinement relation different from trace containment. Our rule is circular, and its soundness proof requires induction on trace trees. The proof is constructive: given simulation relations that witness the simulation preorder between corresponding components of P and Q, we provide a procedure for constructing a witness relation for P< s Q. We also extend our assume-guarantee rule to account for fairness assumptions on transition systems}, author = {Henzinger, Thomas A and Qadeer, Shaz and Rajamani, Sriram and Tasiran, Serdar}, booktitle = {Proceedings of the 2nd International Conference on Formal Methods in Computer-Aided Design}, isbn = {9783540651918}, location = {Palo Alto, CA, United States of America}, pages = {421 -- 432}, publisher = {Springer}, title = {{An assume-guarantee rule for checking simulation}}, doi = {10.1007/3-540-49519-3_27}, volume = {1522}, year = {1998}, } @inproceedings{4488, abstract = {Assume-guarantee reasoning has long been advertised as an important method for decomposing proof obligations in system verification. Refinement mappings (homomorphisms) have long been advertised as an important method for solving the language-inclusion problem in practice. When confronted with large verification problems, we therefore attempted to make use of both techniques. We soon found that rather than offering instant solutions, the success of assume-guarantee reasoning depends critically on the construction of suitable abstraction modules, and the success of refinement checking depends critically on the construction of suitable witness modules. Moreover, as abstractions need to be witnessed, and witnesses abstracted, the process must be iterated. We present here the main lessons we learned from our experiments, in limn of a systematic and structured discipline for the compositional verification of reactive modules. An infrastructure to support this discipline, and automate parts of the verification, has been implemented in the tool Mocha.}, author = {Henzinger, Thomas A and Qadeer, Shaz and Rajamani, Sriram}, booktitle = {Proceedings of the 10th International Conference on Computer Aided Verification}, isbn = {9783540646082}, location = {Vancouver, Canada}, pages = {440 -- 451}, publisher = {Springer}, title = {{You assume, we guarantee: Methodology and case studies}}, doi = {10.1007/BFb0028765}, volume = {1427}, year = {1998}, } @inproceedings{4489, abstract = {Symbolic model checking, which enables the automatic verification of large systems, proceeds by calculating with expressions that represent state sets. Traditionally, symbolic model-checking tools arc based on backward state traversal; their basic operation is the function pre, which given a set of states, returns the set of all predecessor states. This is because specifiers usally employ formalisms with future-time modalities. which are naturally evaluated by iterating applications of pre. It has been recently shown experimentally that symbolic model checking can perform significantly better if it is based, instead, on forward state traversal; in this case, the basic operation is the function post, which given a set of states, returns the set of all successor states. This is because forward state traversal can ensure that only those parts of the state space are explored which are reachable from an initial state and relevant for satisfaction or violation of the specification; that is, errors can be detected as soon as possible. In this paper, we investigate which specifications can be checked by symbolic forward state traversal. We formulate the problems of symbolic backward and forward model checking by means of two -calculi. The pre- calculus is based on the pre operation; the post- calculus, on the post operation. These two -calculi induce query logics, which augment fixpoint expressions with a boolean emptiness query. Using query logics, we are able to relate and compare the symbolic backward and forward approaches. In particular, we prove that all -regular (linear-time) specifications can be expressed as post- queries, and therefore checked using symbolic forward state traversal. On the other hand, we show that there are simple branching-time specifications that cannot be checked in this way.}, author = {Henzinger, Thomas A and Kupferman, Orna and Qadeer, Shaz}, booktitle = {Proceedings of the 10th International Conference on Computer Aided Verification}, isbn = {9783540646082}, location = {Vancouver, Canada}, pages = {195 -- 206}, publisher = {Springer}, title = {{From pre-historic to post-modern symbolic model checking}}, doi = {10.1007/BFb0028745}, volume = {1427}, year = {1998}, } @inproceedings{4490, abstract = {A specification formalism for reactive systems defines a class of Ω-languages. We call a specification formalism fully decidable if it is constructively closed under boolean operations and has a decidable satisfiability (nonemptiness) problem. There are two important, robust classes of Ω-languages that are definable by fully decidable formalisms. The Ω -reqular languages are definable by finite automata, or equivalcntly, by the Sequential Calculus. The counter-free Ω-regular languages are definable by temporal logic, or equivalcntly, by the first-order fragment of the Sequential Calculus. The gap between both classes can be closed by finite counting (using automata connectives), or equivalently, by projection (existential second-order quantification over letters). A specification formalism for real-time systems defines a class of timed Ω-langnages, whose letters have real-numbered time stamps. Two popular ways of specifying timing constraints rely on the use of clocks, and on the use of time bounds for temporal operators. However, temporal logics with clocks or time bounds have undecidable satisfiability problems, and finite automata with clocks (so-called timed automata) are not closed under complement. Therefore, two fully decidable restrictions of these formalisms have been proposed. In the first case, clocks are restricted to event clocks, which measure distances to immediately preceding or succeeding events only. In the second case, time bounds are restricted to nonsingular intervals, which cannot specify the exact punctuality of events. We show that the resulting classes of timed Ω-languages are robust, and we explain their relationship. First, we show that temporal logic with event clocks defines the same class of timed Ω-languages as temporal logic with nonsingular time bounds, and we identify a first-order monadic theory that also defines this class. Second, we show that if the ability of finite counting is added to these formalisms, we obtain the class of timed Ω-languages that are definable by finite automata with event clocks, or equivalently, by a restricted second-order extension of the monadic theory. Third, we show that if projection is added, we obtain the class of timed Ω-languages that are definable by timed automata, or equivalently, by a richer second-order extension of the monadic theory. These results identify three robust classes of timed Ω-languages, of which the third, while popular, is not definable by a, fully decidable formalism. By contrast, the first two classes are definable by fully decidable formalisms from temporal logic, from automata theory, and from monadic logic. Since the gap between these two classes can be closed by finite counting, we dub them the timed Ω-regular languages and the timed counter-free Ω-rcgular languages, respectively.}, author = {Henzinger, Thomas A and Raskin, Jean and Schobbens, Pierre}, booktitle = {Proceedings of the 25th International Colloqium on Automata, Languages and Programming}, isbn = {9783540647812}, location = {Aalborg, Denmark}, pages = {580 -- 591}, publisher = {Springer}, title = {{The regular real-time languages}}, doi = {10.1007/BFb0055086}, volume = {1443}, year = {1998}, } @article{4491, abstract = {We present two methods for translating nonlinear hybrid systems into linear hybrid automata. Properties of the nonlinear systems can then be inferred from the automatic analysis of the translated linear hybrid automata. The first method, called clock translation, replaces constraints on nonlinear variables by constraints on clock variables. The second method, called linear phase-portrait approximation, conservatively overapproximates the phase portrait of a hybrid automaton using piecewise-constant polyhedral differential inclusions. Both methods are sound for safety properties. We illustrate both methods by using HYTECH, a symbolic model checker for linear hybrid automata, to automatically check properties of a nonlinear temperature controller and of a predator-prey ecology}, author = {Henzinger, Thomas A and Ho, Pei and Wong Toi, Howard}, issn = {0018-9162}, journal = {IEEE Transactions on Automatic Control}, number = {4}, pages = {540 -- 554}, publisher = {IEEE}, title = {{Algorithmic analysis of nonlinear hybrid systems}}, doi = {10.1109/9.664156 }, volume = {43}, year = {1998}, } @article{4492, abstract = {Hybrid automata model systems with both digital and analog components, such as embedded control programs. Many verification tasks for such programs can be expressed as reachability problems for hybrid automata. By improving on previous decidability and undecidability results, we identify a boundary between decidability and undecidability for the reachability problem of hybrid automata. On the positive side, we give an (optimal) PSPACE reachability algorithm for the case of initialized rectangular automata, where all analog variables follow independent trajectories within piecewise-linear envelopes and are reinitialized whenever the envelope changes. Our algorithm is based on the construction of a timed automaton that contains all reachability information about a given initialized rectangular automaton. The translation has practical significance for verification, because it guarantees the termination of symbolic procedures for the reachability analysis of initialized rectangular automata. The translation also preserves theω-languages of initialized rectangular automata with bounded nondeterminism. On the negative side, we show that several slight generalizations of initialized rectangular automata lead to an undecidable reachability problem. In particular, we prove that the reachability problem is undecidable for timed automata augmented with a single stopwatch.}, author = {Henzinger, Thomas A and Kopke, Peter and Puri, Anuj and Varaiya, P.}, isbn = {0022-0000}, journal = {Journal of Computer and System Sciences}, number = {1}, pages = {94 -- 124}, publisher = {Elsevier}, title = {{What's decidable about hybrid automata?}}, doi = {10.1006/jcss.1998.1581}, volume = {57}, year = {1998}, } @inproceedings{4515, abstract = {We summarize and reorganize some of the last decade's research on real-time extensions of temporal logic. Our main focus is on tableau constructions for model checking linear temporal formulas with timing constraints. In particular, we find that a great deal of real-time verification can be performed in polynomial space, but also that considerable care must be exercised in order to keep the real-time verification problem in polynomial space, or even decidable.}, author = {Henzinger, Thomas A}, booktitle = {Proceedings of the 9th Interantional Conference on Concurrency Theory}, isbn = {978-3-540-64896-3}, location = {Nice, France}, pages = {439 -- 454}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{It's about time: Real-time logics reviewed}}, doi = {10.1007/BFb0055640}, volume = {1466}, year = {1998}, }