5CINECA Supercomputing Centre. 6University of Modena and Reggio Emilia.7Christian-Albrechts-University Kiel.8Michigan State University. International course and report were conceived by Pietro Cozzini and Glen E. Kellogg. * To whom correspondence should be addressed. For G.E.K.: Department of Medicinal Chemistry, Virginia Commonwealth University, Box 980540, Richmond, VA 23298-0540; (phone) 804-828-6452; (fax) 804-827-3664; (e-mail) glen.kellogg@vcu.edu. For P.C.: Department of General and Inorganic Chemistry, University of Parma, Via G.P. Usberti 17/A 43100, Parma, Italy; (phone) +39-0521-905669; (fax) +39-0521-905556; (e-mail) pietro.cozzini@unipr.it. NIH Public Access IntroductionStructure-based drug discovery has played an important role in medicinal chemistry 1 beginning nearly when the first X-ray crystal structure of the myoglobin and hemoglobin proteins at nearatomic resolution were described by Perutz, Kendrew and colleagues. 2-5 Even though only static structures were (and still generally are) used for most Structure-Based Drug Design (SBDD), and indeed most molecular modeling, the importance of flexibility was recognized immediately: hemoglobin has two rather different structures, "tense" and "relaxed", depending on its oxygenation, although in recent years a family of relaxed hemoglobin structures with different tertiary structure conformations have been reported. 6 In fact, all proteins are inherently flexible systems. This flexibility is frequently essential for function (e.g., as in hemoglobin). Proteins have an intrinsic ability to undergo functionally relevant conformational transitions under native state conditions, 7,8 on a wide range of scales, both in time and space. 9 In adenylate kinase large conformational changes due to movements of the nucleotide 'lids'-rate-limiting for overall catalytic turnover 10,11 -are 'linked' with relatively small-amplitude atomic fluctuations on the ps timescale such that changes in the local backbone conformation are required for lid closure. 12 Nuclear receptors are modular proteins where a significant degree of conformational flexibility is essential to biological function. Most of the pharmacology of nuclear receptor ligands has been discussed on the basis of their ability to stabilize (or displace) a short α-helix segment (known as H12 or AF-2) localized at the carboxy terminus of the receptor in (or from) its conformation in the protein "active" form. 13-15 Available X-ray crystal structures show a surprisingly wide range of structural diversity in ligands binding to, and inhibiting, nuclear receptor proteins such as the farnesoid X-receptor (FXR). 16,17 Protein dynamics is also a key component of intramolecular and intermolecular communication/signaling mechanisms and an essential requirement for the function of Gprotein coupled receptors (GPCRs), which are the largest known superfamily of membrane proteins. GPCRs regulate cell activity by transmitting extracellular signals to the inside of cells and respond to these signals by catalyzing nucleotide e...

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Given the enormous social and health impact of the pandemic triggered by severe acute respiratory syndrome 2 (SARS-CoV-2), the scientific community made a huge effort to provide an immediate response to the challenges posed by Coronavirus disease 2019 (COVID-19). One of the most important proteins of the virus is an enzyme, called 3CLpro or main protease, already identified as an important pharmacological target also in SARS and Middle East respiratory syndrome virus (MERS) viruses. This protein triggers the production of a whole series of enzymes necessary for the virus to carry out its replicating and infectious activities. Therefore, it is crucial to gain a deeper understanding of 3CLpro structure and function in order to effectively target this enzyme. All-atoms molecular dynamics (MD) simulations were performed to examine the different conformational behaviors of the monomeric and dimeric form of SARS-CoV-2 3CLpro apo structure, as revealed by microsecond time scale MD simulations. Our results also shed light on the conformational dynamics of the loop regions at the entry of the catalytic site. Studying, at atomic level, the characteristics of the active site and obtaining information on how the protein can interact with its substrates will allow the design of molecules able to block the enzymatic function crucial for the virus.

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Guaranteed numerical precision of each elementary step in a complex computation has been the mainstay of traditional computing systems for many years. This era, fueled by Moore's law and the constant exponential improvement in computing efficiency, is at its twilight: from tiny nodes of the Internet-of-Things, to large HPC computing centers, sub-picoJoule/operation energy efficiency is essential for practical realizations. To overcome the power wall, a shift from traditional computing paradigms is now mandatory. In this paper we present the driving motivations, roadmap, and expected impact of the European project OPRECOMP. OPRECOMP aims to (i) develop the first complete transprecision computing framework, (ii) apply it to a wide range of hardware platforms, from the sub-milliWatt up to the MegaWatt range, and (iii) demonstrate impact in a wide range of computational domains, spanning IoT, Big Data Analytics, Deep Learning, and HPC simulations. By combining together into a seamless design transprecision advances in devices, circuits, software tools, and algorithms, we expect to achieve major energy efficiency improvements, even when there is no freedom to relax end-to-end application quality of results. Indeed, OPRECOMP aims at demolishing the ultraconservative "precise" computing abstraction, replacing it with a more flexible and efficient one, namely transprecision computing.

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ABSTRACT:A common format for quantum chemistry (QC), enhancing code interoperability and communication between different programs, has been designed and implemented. An XML-based format, QC-ML, is presented for representing quantities such as geometry, basis set, and so on, while an HDF5-based format is presented for the storage of large binary data files. Some preliminary applications that use the format have been implemented and are also described. This activity was carried out within the COST in Chemistry D23 project "MetaChem," in the Working Group "A metalaboratory for code integration in ab initio methods."

The ultimate aim of the EU-funded ImmunoGrid project is to develop a natural-scale model of the human immune system-that is, one that reflects both the diversity and the relative proportions of the molecules and cells that comprise it-together with the * Author for correspondence (a.shepherd@mail.cryst.bbk.ac.uk). † The authors of this paper belong to the ImmunoGrid Consortium. grid infrastructure necessary to apply this model to specific applications in the field of immunology. These objectives present the ImmunoGrid Consortium with formidable challenges in terms of complexity of the immune system, our partial understanding about how the immune system works, the lack of reliable data and the scale of computational resources required.In this paper, we explain the key challenges and the approaches adopted to overcome them. We also consider wider implications for the present ambitious plans to develop natural-scale, integrated models of the human body that can make contributions to personalized health care, such as the European Virtual Physiological Human initiative.Finally, we ask a key question: How long will it take us to resolve these challenges and when can we expect to have fully functional models that will deliver health-care benefits in the form of personalized care solutions and improved disease prevention?