Enumeration, conformation sampling and population of libraries of peptide macrocycles for the search of chemotherapeutic cardioprotection agents

Peptides are uniquely endowed with features that allow them to perturb previously difficult to drug biomolecular targets. Peptide macrocycles in particular have seen a flurry of recent interest due to their enhanced bioavailability, tunability and specificity. Although these properties make them attractive hit-candidates in early stage drug discovery, knowing which peptides to pursue is non‐trivial due to the magnitude of the peptide sequence space. Computational screening approaches show promise in their ability to address the size of this search space but suffer from their inability to accurately interrogate the conformational landscape of peptide macrocycles. We developed an in‐silico compound enumerator that was tasked with populating a conformationally laden peptide virtual library. This library was then used in the search for cardio‐protective agents (that may be administered, reducing tissue damage during reperfusion after ischemia (heart attacks)). Our enumerator successfully generated a library of 15.2 billion compounds, requiring the use of compression algorithms, conformational sampling protocols and management of aggregated compute resources in the context of a local cluster. In the absence of experimental biophysical data, we performed biased sampling during alchemical molecular dynamics simulations in order to observe cyclophilin‐D perturbation by cyclosporine A and its mitochondrial targeted analogue. Reliable intermediate state averaging through a WHAM analysis of the biased dynamic pulling simulations confirmed that the cardio‐protective activity of cyclosporine A was due to its mitochondrial targeting. Paralleltempered solution molecular dynamics in combination with efficient clustering isolated the essential dynamics of a cyclic peptide scaffold. The rapid enumeration of skeletons from these essential dynamics gave rise to a conformation laden virtual library of all the 15.2 Billion unique cyclic peptides (given the limits on peptide sequence imposed). Analysis of this library showed the exact extent of physicochemical properties covered, relative to the bare scaffold precursor. Molecular docking of a subset of the virtual library against cyclophilin‐D showed significant improvements in affinity to the target (relative to cyclosporine A). The conformation laden virtual library, accessed by our methodology, provided derivatives that were able to make many interactions per peptide with the cyclophilin‐D target. Machine learning methods showed promise in the training of Support Vector Machines for synthetic feasibility prediction for this library. The synergy between enumeration and conformational sampling greatly improves the performance of this library during virtual screening, even when only a subset is used

Vector Semantics

This open access book introduces Vector semantics, which links the formal theory of word vectors to the cognitive theory of linguistics. The computational linguists and deep learning researchers who developed word vectors have relied primarily on the ever-increasing availability of large corpora and of computers with highly parallel GPU and TPU compute engines, and their focus is with endowing computers with natural language capabilities for practical applications such as machine translation or question answering. Cognitive linguists investigate natural language from the perspective of human cognition, the relation between language and thought, and questions about conceptual universals, relying primarily on in-depth investigation of language in use. In spite of the fact that these two schools both have ‘linguistics’ in their name, so far there has been very limited communication between them, as their historical origins, data collection methods, and conceptual apparatuses are quite different. Vector semantics bridges the gap by presenting a formal theory, cast in terms of linear polytopes, that generalizes both word vectors and conceptual structures, by treating each dictionary definition as an equation, and the entire lexicon as a set of equations mutually constraining all meanings

The Future of Humanoid Robots

This book provides state of the art scientific and engineering research findings and developments in the field of humanoid robotics and its applications. It is expected that humanoids will change the way we interact with machines, and will have the ability to blend perfectly into an environment already designed for humans. The book contains chapters that aim to discover the future abilities of humanoid robots by presenting a variety of integrated research in various scientific and engineering fields, such as locomotion, perception, adaptive behavior, human-robot interaction, neuroscience and machine learning. The book is designed to be accessible and practical, with an emphasis on useful information to those working in the fields of robotics, cognitive science, artificial intelligence, computational methods and other fields of science directly or indirectly related to the development and usage of future humanoid robots. The editor of the book has extensive R&D experience, patents, and publications in the area of humanoid robotics, and his experience is reflected in editing the content of the book

Vector Semantics

This open access book introduces Vector semantics, which links the formal theory of word vectors to the cognitive theory of linguistics. The computational linguists and deep learning researchers who developed word vectors have relied primarily on the ever-increasing availability of large corpora and of computers with highly parallel GPU and TPU compute engines, and their focus is with endowing computers with natural language capabilities for practical applications such as machine translation or question answering. Cognitive linguists investigate natural language from the perspective of human cognition, the relation between language and thought, and questions about conceptual universals, relying primarily on in-depth investigation of language in use. In spite of the fact that these two schools both have ‘linguistics’ in their name, so far there has been very limited communication between them, as their historical origins, data collection methods, and conceptual apparatuses are quite different. Vector semantics bridges the gap by presenting a formal theory, cast in terms of linear polytopes, that generalizes both word vectors and conceptual structures, by treating each dictionary definition as an equation, and the entire lexicon as a set of equations mutually constraining all meanings

Stabilization of cascaded nonlinear systems under sampling and delays

Over the last decades, the methodologies of dynamical systems and control theory have been playing an increasingly relevant role in a lot of situations of practical interest. Though, a lot of theoretical problem still remain unsolved. Among all, the ones concerning stability and stabilization are of paramount importance. In order to stabilize a physical (or not) system, it is necessary to acquire and interpret heterogeneous information on its behavior in order to correctly intervene on it. In general, those information are not available through a continuous flow but are provided in a synchronous or asynchronous way. This issue has to be unavoidably taken into account for the design of the control action. In a very natural way, all those heterogeneities define an hybrid system characterized by both continuous and discrete dynamics. This thesis is contextualized in this framework and aimed at proposing new methodologies for the stabilization of sampled-data nonlinear systems with focus toward the stabilization of cascade dynamics. In doing so, we shall propose a small number of tools for constructing sampled-data feedback laws stabilizing the origin of sampled-data nonlinear systems admitting cascade interconnection representations. To this end, we shall investigate on the effect of sampling on the properties of the continuous-time system while enhancing design procedures requiring no extra assumptions over the sampled-data equivalent model. Finally, we shall show the way sampling positively affects nonlinear retarded dynamics affected by a fixed and known time-delay over the input signal by enforcing on the implicit cascade representation the sampling process induces onto the retarded system

Understanding Quantum Technologies 2022

Understanding Quantum Technologies 2022 is a creative-commons ebook that provides a unique 360 degrees overview of quantum technologies from science and technology to geopolitical and societal issues. It covers quantum physics history, quantum physics 101, gate-based quantum computing, quantum computing engineering (including quantum error corrections and quantum computing energetics), quantum computing hardware (all qubit types, including quantum annealing and quantum simulation paradigms, history, science, research, implementation and vendors), quantum enabling technologies (cryogenics, control electronics, photonics, components fabs, raw materials), quantum computing algorithms, software development tools and use cases, unconventional computing (potential alternatives to quantum and classical computing), quantum telecommunications and cryptography, quantum sensing, quantum technologies around the world, quantum technologies societal impact and even quantum fake sciences. The main audience are computer science engineers, developers and IT specialists as well as quantum scientists and students who want to acquire a global view of how quantum technologies work, and particularly quantum computing. This version is an extensive update to the 2021 edition published in October 2021.Comment: 1132 pages, 920 figures, Letter forma