Metadynamics with Discriminants: a Tool for Understanding Chemistry
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Neural Networks Based Variationally Enhanced Sampling
NEURAL NETWORKS BASED VARIATIONALLY ENHANCED SAMPLING A PREPRINT Luigi Bonati Department of Physics, ETH Zurich, 8092 Zurich, Switzerland and Institute of Computational Sciences, Università della Svizzera italiana, via G. Buffi 13, 6900 Lugano, Switzerland Yue-Yu Zhang Department of Chemistry and Applied Biosciences, ETH Zurich, 8092 Zurich, Switzerland and Institute of Computational Sciences, Università della Svizzera italiana, via G. Buffi 13, 6900 Lugano, Switzerland Michele Parrinello Department of Chemistry and Applied Biosciences, ETH Zurich, 8092 Zurich, Switzerland, Institute of Computational Sciences, Università della Svizzera italiana, via G. Buffi 13, 6900 Lugano, Switzerland, and Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy September 25, 2019 ABSTRACT Sampling complex free energy surfaces is one of the main challenges of modern atomistic simulation methods. The presence of kinetic bottlenecks in such surfaces often renders a direct approach useless. A popular strategy is to identify a small number of key collective variables and to introduce a bias potential that is able to favor their fluctuations in order to accelerate sampling. Here we propose to use machine learning techniques in conjunction with the recent variationally enhanced sampling method [Valsson and Parrinello, Phys. Rev. Lett. 2014] in order to determine such potential. This is achieved by expressing the bias as a neural network. The parameters are determined in a variational learning scheme aimed at minimizing an appropriate functional. This required the development of a new and more efficient minimization technique. The expressivity of neural networks allows representing rapidly varying free energy surfaces, removes boundary effects artifacts and allows several collective variables to be handled. -
Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development
processes Review Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development Outi M. H. Salo-Ahen 1,2,* , Ida Alanko 1,2, Rajendra Bhadane 1,2 , Alexandre M. J. J. Bonvin 3,* , Rodrigo Vargas Honorato 3, Shakhawath Hossain 4 , André H. Juffer 5 , Aleksei Kabedev 4, Maija Lahtela-Kakkonen 6, Anders Støttrup Larsen 7, Eveline Lescrinier 8 , Parthiban Marimuthu 1,2 , Muhammad Usman Mirza 8 , Ghulam Mustafa 9, Ariane Nunes-Alves 10,11,* , Tatu Pantsar 6,12, Atefeh Saadabadi 1,2 , Kalaimathy Singaravelu 13 and Michiel Vanmeert 8 1 Pharmaceutical Sciences Laboratory (Pharmacy), Åbo Akademi University, Tykistökatu 6 A, Biocity, FI-20520 Turku, Finland; ida.alanko@abo.fi (I.A.); rajendra.bhadane@abo.fi (R.B.); parthiban.marimuthu@abo.fi (P.M.); atefeh.saadabadi@abo.fi (A.S.) 2 Structural Bioinformatics Laboratory (Biochemistry), Åbo Akademi University, Tykistökatu 6 A, Biocity, FI-20520 Turku, Finland 3 Faculty of Science-Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands; [email protected] 4 Swedish Drug Delivery Forum (SDDF), Department of Pharmacy, Uppsala Biomedical Center, Uppsala University, 751 23 Uppsala, Sweden; [email protected] (S.H.); [email protected] (A.K.) 5 Biocenter Oulu & Faculty of Biochemistry and Molecular Medicine, University of Oulu, Aapistie 7 A, FI-90014 Oulu, Finland; andre.juffer@oulu.fi 6 School of Pharmacy, University of Eastern Finland, FI-70210 Kuopio, Finland; maija.lahtela-kakkonen@uef.fi (M.L.-K.); tatu.pantsar@uef.fi -
Electronic Supporting Information a New Class of Soluble and Stable Transition-Metal-Substituted Polyoxoniobates: [Cr2(OH)4Nb10o
Electronic Supplementary Material (ESI) for Dalton Transactions This journal is © The Royal Society of Chemistry 2012 Electronic Supporting Information A New Class of Soluble and Stable Transition-Metal-Substituted Polyoxoniobates: [Cr2(OH)4Nb10O30]8-. Jung-Ho Son, C. André Ohlin and William H. Casey* A) Computational Results The two most interesting aspects of this new polyoxoanion is the inclusion of a more redox active metal and the optical activity in the visible region. For these reasons we in particular wanted to explore whether it was possible to readily and routinely predict the location of the absorbance bands of this type of compound. Also, owing to the difficulty in isolating the oxidised and reduced forms of the central polyanion dichromate species, we employed computations at the density functional theory (DFT) level to get a better idea of the potential characteristics of these forms. Structures were optimised for anti-parallel and parallel electronic spin alignments, and for both high and low spin cases where relevant. Intermediate spin configurations were 8- II III also tested for [Cr2(OH)4Nb10O30] . As expected, the high spin form of the Cr Cr complex was favoured (Table S1, below). DFT overestimates the bond lengths in general, but gives a good picture of the general distortion of the octahedral chromium unit, and in agreement with the crystal structure predicts that the shortest bond is the Cr-µ2-O bond trans from the central µ6- oxygen in the Lindqvist unit, and that the (Nb-)µ2-O-Cr-µ4-O(-Nb,Nb,Cr) angle is smaller by ca 5˚ from the ideal 180˚. -
Computer-Assisted Catalyst Development Via Automated Modelling of Conformationally Complex Molecules
www.nature.com/scientificreports OPEN Computer‑assisted catalyst development via automated modelling of conformationally complex molecules: application to diphosphinoamine ligands Sibo Lin1*, Jenna C. Fromer2, Yagnaseni Ghosh1, Brian Hanna1, Mohamed Elanany3 & Wei Xu4 Simulation of conformationally complicated molecules requires multiple levels of theory to obtain accurate thermodynamics, requiring signifcant researcher time to implement. We automate this workfow using all open‑source code (XTBDFT) and apply it toward a practical challenge: diphosphinoamine (PNP) ligands used for ethylene tetramerization catalysis may isomerize (with deleterious efects) to iminobisphosphines (PPNs), and a computational method to evaluate PNP ligand candidates would save signifcant experimental efort. We use XTBDFT to calculate the thermodynamic stability of a wide range of conformationally complex PNP ligands against isomeriation to PPN (ΔGPPN), and establish a strong correlation between ΔGPPN and catalyst performance. Finally, we apply our method to screen novel PNP candidates, saving signifcant time by ruling out candidates with non‑trivial synthetic routes and poor expected catalytic performance. Quantum mechanical methods with high energy accuracy, such as density functional theory (DFT), can opti- mize molecular input structures to a nearby local minimum, but calculating accurate reaction thermodynamics requires fnding global minimum energy structures1,2. For simple molecules, expert intuition can identify a few minima to focus study on, but an alternative approach must be considered for more complex molecules or to eventually fulfl the dream of autonomous catalyst design 3,4: the potential energy surface must be frst surveyed with a computationally efcient method; then minima from this survey must be refned using slower, more accurate methods; fnally, for molecules possessing low-frequency vibrational modes, those modes need to be treated appropriately to obtain accurate thermodynamic energies 5–7. -
Dalton2018.0 – Lsdalton Program Manual
Dalton2018.0 – lsDalton Program Manual V. Bakken, A. Barnes, R. Bast, P. Baudin, S. Coriani, R. Di Remigio, K. Dundas, P. Ettenhuber, J. J. Eriksen, L. Frediani, D. Friese, B. Gao, T. Helgaker, S. Høst, I.-M. Høyvik, R. Izsák, B. Jansík, F. Jensen, P. Jørgensen, J. Kauczor, T. Kjærgaard, A. Krapp, K. Kristensen, C. Kumar, P. Merlot, C. Nygaard, J. Olsen, E. Rebolini, S. Reine, M. Ringholm, K. Ruud, V. Rybkin, P. Sałek, A. Teale, E. Tellgren, A. Thorvaldsen, L. Thøgersen, M. Watson, L. Wirz, and M. Ziolkowski Contents Preface iv I lsDalton Installation Guide 1 1 Installation of lsDalton 2 1.1 Installation instructions ............................. 2 1.2 Hardware/software supported .......................... 2 1.3 Source files .................................... 2 1.4 Installing the program using the Makefile ................... 3 1.5 The Makefile.config ................................ 5 1.5.1 Intel compiler ............................... 5 1.5.2 Gfortran/gcc compiler .......................... 9 1.5.3 Using 64-bit integers ........................... 12 1.5.4 Using Compressed-Sparse Row matrices ................ 13 II lsDalton User’s Guide 14 2 Getting started with lsDalton 15 2.1 The Molecule input file ............................ 16 2.1.1 BASIS ................................... 17 2.1.2 ATOMBASIS ............................... 18 2.1.3 User defined basis sets .......................... 19 2.2 The LSDALTON.INP file ............................ 21 3 Interfacing to lsDalton 24 3.1 The Grand Canonical Basis ........................... 24 3.2 Basisset and Ordering .............................. 24 3.3 Normalization ................................... 25 i CONTENTS ii 3.4 Matrix File Format ................................ 26 3.5 The lsDalton library bundle .......................... 27 III lsDalton Reference Manual 29 4 List of lsDalton keywords 30 4.1 **GENERAL ................................... 31 4.1.1 *TENSOR ............................... -
Structural Ensembles of Intrinsically Disordered Proteins Depend Strongly on Force Field: a Comparison to Experiment Sarah Rauscher,*,† Vytautas Gapsys,† Michal J
Article pubs.acs.org/JCTC Structural Ensembles of Intrinsically Disordered Proteins Depend Strongly on Force Field: A Comparison to Experiment Sarah Rauscher,*,† Vytautas Gapsys,† Michal J. Gajda,‡ Markus Zweckstetter,‡,§,∥ Bert L. de Groot,† and Helmut Grubmüller† † Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Göttingen 37077, Germany ‡ Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen 37077, Germany § German Center for Neurodegenerative Diseases (DZNE), Göttingen 37077, Germany ∥ Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University Medical Center, Göttingen 37073, Germany *S Supporting Information ABSTRACT: Intrinsically disordered proteins (IDPs) are notoriously challenging to study both experimentally and computationally. The structure of IDPs cannot be described by a single conformation but must instead be described as an ensemble of interconverting conformations. Atomistic simu- lations are increasingly used to obtain such IDP conformational ensembles. Here, we have compared the IDP ensembles generated by eight all-atom empirical force fields against primary small-angle X-ray scattering (SAXS) and NMR data. Ensembles obtained with different force fields exhibit marked differences in chain dimensions, hydrogen bonding, and secondary structure content. These differences are unexpect- edly large: changing the force field is found to have a stronger effect on secondary structure content than changing the entire peptide sequence. The CHARMM 22* ensemble performs best in this force field comparison: it has the lowest error in chemical shifts and J-couplings and agrees well with the SAXS data. A high population of left-handed α-helix is present in the CHARMM 36 ensemble, which is inconsistent with measured scalar couplings. -
Quantum Chemistry on a Grid
Quantum Chemistry on a Grid Lucas Visscher Vrije Universiteit Amsterdam 1 Outline Why Quantum Chemistry needs to be gridified Computational Demands Other requirements What may be expected ? Program descriptions Dirac • Organization • Distributed development and testing Dalton Amsterdam Density Functional (ADF) An ADF-Dalton-Dirac grid driver Design criteria Current status Quantum Chemistry on the Grid, 08-11-2005 L. Visscher, Vrije Universiteit Amsterdam 2 Computational (Quantum) Chemistry QC is traditionally run on supercomputers Large fraction of the total supercomputer time annually allocated Characteristics Compute Time scales cubically or higher with number of atoms treated. Typical : a few hours to several days on a supercomputer Memory Usage scales quadratically or higher with number of atoms. Typical : A few hundred MB till tens of GB Data Storage variable. Typical: tens of Mb till hundreds of GB. Communication • Often serial (one-processor) runs in production work • Parallelization needs sufficient band width. Typical lower limit 100 Mb/s. Quantum Chemistry on the Grid, 08-11-2005 L. Visscher, Vrije Universiteit Amsterdam 3 Changing paradigms in quantum chemistry Computable molecules are often already “large” enough Many degrees of freedom Search for global minimum energy is less important Statistical sampling of different conformations is desired Let the nuclei move, follow molecules that evolve in time 2 steps : (Quantum) dynamics on PES 1 step : Classical dynamics with forces computed via QM Changing characteristics General: more similar calculations Compute time : Increases : more calculations Memory usage : Stays constant : typical size remains the same Data storage : Decreases : intermediate results are less important Communication: Decreases : only start-up data and final result Quantum Chemistry on the Grid, 08-11-2005 L. -
Molecular Dynamics Free Energy Simulations Reveal the Mechanism for the Antiviral Resistance of the M66I HIV-1 Capsid Mutation
viruses Article Molecular Dynamics Free Energy Simulations Reveal the Mechanism for the Antiviral Resistance of the M66I HIV-1 Capsid Mutation Qinfang Sun 1 , Ronald M. Levy 1,*, Karen A. Kirby 2,3 , Zhengqiang Wang 4 , Stefan G. Sarafianos 2,3 and Nanjie Deng 5,* 1 Center for Biophysics and Computational Biology and Department of Chemistry, Temple University, Philadelphia, PA 19122, USA; [email protected] 2 Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA; [email protected] (K.A.K.); stefanos.sarafi[email protected] (S.G.S.) 3 Children’s Healthcare of Atlanta, Atlanta, GA 30322, USA 4 Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA; [email protected] 5 Department of Chemistry and Physical Sciences, Pace University, New York, NY 10038, USA * Correspondence: [email protected] (R.M.L.); [email protected] (N.D.) Abstract: While drug resistance mutations can often be attributed to the loss of direct or solvent- mediated protein−ligand interactions in the drug-mutant complex, in this study we show that a resistance mutation for the picomolar HIV-1 capsid (CA)-targeting antiviral (GS-6207) is mainly due to the free energy cost of the drug-induced protein side chain reorganization in the mutant protein. Among several mutations, M66I causes the most suppression of the GS-6207 antiviral activity Citation: Sun, Q.; Levy, R.M.; Kirby, (up to ~84,000-fold), and only 83- and 68-fold reductions for PF74 and ZW-1261, respectively. To K.A.; Wang, Z.; Sarafianos, S.G.; understand the molecular basis of this drug resistance, we conducted molecular dynamics free energy Deng, N. -
Multiscale Simulations of Intrinsically Disordered Proteins
University of Massachusetts Amherst ScholarWorks@UMass Amherst Doctoral Dissertations Dissertations and Theses July 2019 Multiscale Simulations of Intrinsically Disordered Proteins Xiaorong Liu University of Massachusetts Amherst Follow this and additional works at: https://scholarworks.umass.edu/dissertations_2 Part of the Biophysics Commons, Physical Chemistry Commons, and the Structural Biology Commons Recommended Citation Liu, Xiaorong, "Multiscale Simulations of Intrinsically Disordered Proteins" (2019). Doctoral Dissertations. 1565. https://doi.org/10.7275/14020756 https://scholarworks.umass.edu/dissertations_2/1565 This Open Access Dissertation is brought to you for free and open access by the Dissertations and Theses at ScholarWorks@UMass Amherst. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of ScholarWorks@UMass Amherst. For more information, please contact [email protected]. Multiscale Simulations of Intrinsically Disordered Proteins A Dissertation Presented by XIAORONG LIU Submitted to the Graduate School of the University of Massachusetts Amherst in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY May 2019 Chemistry © Copyright by Xiaorong Liu 2019 All Rights Reserved Multiscale Simulations of Intrinsically Disordered Proteins A Dissertation Presented by XIAORONG LIU Approved as to style and content by: ____________________________________ Jianhan Chen, Chair ____________________________________ Scott Auerbach, Member ____________________________________ Craig Martin, Member ____________________________________ Li-Jun Ma, Member __________________________________ Richard Vachet, Department Head Department of Chemistry DEDICATION To my parents, husband, advisor and other educators who light the way forward for me. ACKNOWLEDGMENTS First and foremost, I would like to express my wholehearted gratitude to my research advisor Dr. Jianhan Chen. Dr. Chen is a great scientist, who is extremely knowledgeable, wise and passionate about science. -
Computational Studies of the Unusual Water Adduct [Cp2time (OH2)]: the Roles of the Solvent and the Counterion
Dalton Transactions View Article Online PAPER View Journal | View Issue Computational studies of the unusual water + adduct [Cp2TiMe(OH2)] : the roles of the Cite this: Dalton Trans., 2014, 43, 11195 solvent and the counterion† Jörg Saßmannshausen + The recently reported cationic titanocene complex [Cp2TiMe(OH2)] was subjected to detailed computational studies using density functional theory (DFT). The calculated NMR spectra revealed the importance of including the anion and the solvent (CD2Cl2) in order to calculate spectra which were in good agreement Received 29th January 2014, with the experimental data. Specifically, two organic solvent molecules were required to coordinate to Accepted 19th March 2014 the two hydrogens of the bound OH2 in order to achieve such agreement. Further elaboration of the role DOI: 10.1039/c4dt00310a of the solvent led to Bader’s QTAIM and natural bond order calculations. The zirconocene complex + www.rsc.org/dalton [Cp2ZrMe(OH2)] was simulated for comparison. Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Introduction Group 4 metallocenes have been the workhorse for a number of reactions for some decades now. In particular the cationic + compounds [Cp2MR] (M = Ti, Zr, Hf; R = Me, CH2Ph) are believed to be the active catalysts for a number of polymeriz- – ation reactions such as Kaminsky type α-olefin,1 10 11–15 16–18 This article is licensed under a carbocationic or ring-opening lactide polymerization. For these highly electrophilic cationic compounds, water is usually considered a poison as it leads to catalyst decompo- sition. In this respect it was quite surprising that Baird Open Access Article. Published on 21 March 2014. -
1 Installation Guide for Columbus Version 7.1 with Openmolcas Support (Colmol-2.1.0)
1 Installation Guide for Columbus Version 7.1 with OpenMolcas Support (colmol-2.1.0) 1.1 Overview Columbus and Molcas cooperate by exchanging well-defined, transferable quantities, specif- ically AO integrals, AO density matrices and MO coefficients in the native Molcas format by using library functions from the Molcas library. Additionally, the RunFile is processed, which is used by Molcas to store additional information often required to be passed in between dif- ferent Molcas modules. Molcas provides some mechanism to incorporate external programs and making them accessible through the standard Molcas input file. Since it is necessary to link a portion of the Molcas library, both Columbus and Molcas must be compiled and linked in a compatible way, that is to say (i) the same compilers and (ii) compatible compiler options. Hence, both codes cooperate on a binary level and do not rely on some file conversion utilities. Please note, that the Molcas library is frequently restructured, so that files produced with a previous version may or may not be compatible with the current version of Molcas (cf. page 4). Additionally, there are now two molcas driver utilities: molcas.exe in Molcas-8.2 developer version and pymolcas in the OpenMolcas version, which may not behave exactly the same way. 1.2 New Features Primarily, rewritten versions of the SCF, MCSCF, AO-MO transformation and CI-gradient code are introduced. With exception of the CI gradient code, all codes are now parallel and make extensive use of shared memory and much more efficient intermediate data storage. The same driver (columbus.exe) now also supports an old modified version of the dalton code (affecting primarily the integral and density matrix handling and storage format in the old HERMIT and ABACUS code portions). -
A Summary of ERCAP Survey of the Users of Top Chemistry Codes
A survey of codes and algorithms used in NERSC chemical science allocations Lin-Wang Wang NERSC System Architecture Team Lawrence Berkeley National Laboratory We have analyzed the codes and their usages in the NERSC allocations in chemical science category. This is done mainly based on the ERCAP NERSC allocation data. While the MPP hours are based on actually ERCAP award for each account, the time spent on each code within an account is estimated based on the user’s estimated partition (if the user provided such estimation), or based on an equal partition among the codes within an account (if the user did not provide the partition estimation). Everything is based on 2007 allocation, before the computer time of Franklin machine is allocated. Besides the ERCAP data analysis, we have also conducted a direct user survey via email for a few most heavily used codes. We have received responses from 10 users. The user survey not only provide us with the code usage for MPP hours, more importantly, it provides us with information on how the users use their codes, e.g., on which machine, on how many processors, and how long are their simulations? We have the following observations based on our analysis. (1) There are 48 accounts under chemistry category. This is only second to the material science category. The total MPP allocation for these 48 accounts is 7.7 million hours. This is about 12% of the 66.7 MPP hours annually available for the whole NERSC facility (not accounting Franklin). The allocation is very tight. The majority of the accounts are only awarded less than half of what they requested for.