Abundance of intrinsic disorder in SV-IV, a multifunctional androgen-dependent protein secreted from rat seminal vesicle

The potent immunomodulatory, anti-inflammatory and procoagulant properties of the
protein no. 4 secreted from the rat seminal vesicle epithelium (SV-IV) have been
previously found to be modulated by a supramolecular monomer-trimer equilibrium.
More structural details that integrate experimental data into a predictive framework
have recently been reported. Unfortunately, homology modelling and fold-recognition
strategies were not successful in creating a theoretical model of the structural
organization of SV-IV. It was inferred that the global structure of SV-IV is not similar
to any protein of known three-dimensional structure. Reversing the classical approach
to the sequence-structure-function paradigm, in this paper we report on novel
information obtained by comparing physicochemical parameters of SV-IV with two
datasets made of intrinsically unfolded and ideally globular proteins. In addition, we
have analysed the SV-IV sequence by several publicly available disorder-oriented
predictors. Overall, disorder predictions and a re-examination of existing experimental
data strongly suggest that SV-IV needs large plasticity to efficiently interact with the
different targets that characterize its multifaceted biological function and should be
therefore better classified as an intrinsically disordered protein

Timing-Driven Macro Placement

Placement is an important step in the process of finding physical layouts for electronic computer chips. The basic task during placement is to arrange the building blocks of the chip, the circuits, disjointly within a given chip area. Furthermore, such positions should result in short circuit interconnections which can be routed easily and which ensure all signals arrive in time. This dissertation mostly focuses on macros, the largest circuits on a chip. In order to optimize timing characteristics during macro placement, we propose a new optimistic timing model based on geometric distance constraints. This model can be computed and evaluated efficiently in order to predict timing traits accurately in practice. Packing rectangles disjointly remains strongly NP-hard under slack maximization in our timing model. Despite of this we develop an exact, linear time algorithm for special cases. The proposed timing model is incorporated into BonnMacro, the macro placement component of the BonnTools physical design optimization suite developed at the Research Institute for Discrete Mathematics. Using efficient formulations as mixed-integer programs we can legalize macros locally while optimizing timing. This results in the first timing-aware macro placement tool. In addition, we provide multiple enhancements for the partitioning-based standard circuit placement algorithm BonnPlace. We find a model of partitioning as minimum-cost flow problem that is provably as small as possible using which we can avoid running time intensive instances. Moreover we propose the new global placement flow Self-Stabilizing BonnPlace. This approach combines BonnPlace with a force-directed placement framework. It provides the flexibility to optimize the two involved objectives, routability and timing, directly during placement. The performance of our placement tools is confirmed on a large variety of academic benchmarks as well as real-world designs provided by our industrial partner IBM. We reduce running time of partitioning significantly and demonstrate that Self-Stabilizing BonnPlace finds easily routable placements for challenging designs – even when simultaneously optimizing timing objectives. BonnMacro and Self-Stabilizing BonnPlace can be combined to the first timing-driven mixed-size placement flow. This combination often finds placements with competitive timing traits and even outperforms solutions that have been determined manually by experienced designers

Complex macrocycle exploration: parallel, heuristic, and constraint-based conformer generation using ForceGen.

ForceGen is a template-free, non-stochastic approach for 2D to 3D structure generation and conformational elaboration for small molecules, including both non-macrocycles and macrocycles. For conformational search of non-macrocycles, ForceGen is both faster and more accurate than the best of all tested methods on a very large, independently curated benchmark of 2859 PDB ligands. In this study, the primary results are on macrocycles, including results for 431 unique examples from four separate benchmarks. These include complex peptide and peptide-like cases that can form networks of internal hydrogen bonds. By making use of new physical movements ("flips" of near-linear sub-cycles and explicit formation of hydrogen bonds), ForceGen exhibited statistically significantly better performance for overall RMS deviation from experimental coordinates than all other approaches. The algorithmic approach offers natural parallelization across multiple computing-cores. On a modest multi-core workstation, for all but the most complex macrocycles, median wall-clock times were generally under a minute in fast search mode and under 2 min using thorough search. On the most complex cases (roughly cyclic decapeptides and larger) explicit exploration of likely hydrogen bonding networks yielded marked improvements, but with calculation times increasing to several minutes and in some cases to roughly an hour for fast search. In complex cases, utilization of NMR data to constrain conformational search produces accurate conformational ensembles representative of solution state macrocycle behavior. On macrocycles of typical complexity (up to 21 rotatable macrocyclic and exocyclic bonds), design-focused macrocycle optimization can be practically supported by computational chemistry at interactive time-scales, with conformational ensemble accuracy equaling what is seen with non-macrocyclic ligands. For more complex macrocycles, inclusion of sparse biophysical data is a helpful adjunct to computation