The CECAM Electronic Structure Library and the modular software development paradigm

First-principles electronic structure calculations are very widely used thanks to the many successful software packages available. Their traditional coding paradigm is monolithic, i.e., regardless of how modular its internal structure may be, the code is built independently from others, from the compiler up, with the exception of linear-algebra and message-passing libraries. This model has been quite successful for decades. The rapid progress in methodology, however, has resulted in an ever increasing complexity of those programs, which implies a growing amount of replication in coding and in the recurrent re-engineering needed to adapt to evolving hardware architecture. The Electronic Structure Library (\esl) was initiated by CECAM (European Centre for Atomic and Molecular Calculations) to catalyze a paradigm shift away from the monolithic model and promote modularization, with the ambition to extract common tasks from electronic structure programs and redesign them as free, open-source libraries. They include ``heavy-duty'' ones with a high degree of parallelisation, and potential for adaptation to novel hardware within them, thereby separating the sophisticated computer science aspects of performance optimization and re-engineering from the computational science done by scientists when implementing new ideas. It is a community effort, undertaken by developers of various successful codes, now facing the challenges arising in the new model. This modular paradigm will improve overall coding efficiency and enable specialists (computer scientists or computational scientists) to use their skills more effectively. It will lead to a more sustainable and dynamic evolution of software as well as lower barriers to entry for new developers

MIST: a portable and efficient toolkit for molecular dynamics integration algorithm development

The main contribution of this thesis is MIST, the Molecular Integration Simula- tion Toolkit, a lightweight and efficient software library written in C++ which provides an abstract interface to common Molecular Dynamics codes, enabling rapid and portable development of new integration schemes for Molecular Dynamics. The initial release provides plug-in interfaces to NAMD-Lite, GROMACS, Amber and LAMMPS and includes several standard integration schemes, a constraint solver, temperature control using Langevin Dynamics, temperature and pressure control using Nosé-Hoover chains, and five advanced sampling schemes. I describe the architecture, functionality and internal details of the library and the C and Fortran APIs which can be used to interface additional MD codes to MIST. As an example to future developers, each of the existing plug-ins and the integrators that are included with MIST are described. Brief instructions for compilation and use of the library are also given as a reference to users. The library is designed to be expressive, portable and performant, and I show via a range of test systems that MIST introduces negligible overheads for serial, parallel, and GPU-accelerated cases, except for Amber where the native integrators run directly on the GPU itself, but only run on the CPU in MIST. The capabilities of MIST for production-quality simulations are demonstrated through the use of a simulated tempering simulation to study the free energy landscape of Alanine-12 in both vacuum and detailed solvent conditions. I also present the evaluation and application of force-field and ab initio Molecular Dynamics to study the structural properties and behaviour of olivine melts. Three existing classical potentials for fayalite are tested and found to give lattice parameters and Radial Distribution Functions in good agreement with experimental data. For forsterite, lattice parameters at ambient pressure and temperature are slightly over-predicted by simulation (similar to other reported results in the literature). Likewise, higher-than expected thermal expansion coefficients and heat capacities are obtained from both ab initio and classical methods. The structure of both the crystal and melt are found to be in good agreement with experimental data. Several methodological improvements which could improve the accuracy of melting point determination and the thermal expansion coefficients are discussed

Computational Methodologies for the Simulation and Analysis of Low-frequency Vibrations in Molecular Crystals

Quantum mechanical models are used to calculate a host of physical phenomena in molecular solids ranging from mechanical elasticity to the energetic stability ordering of polymorphs. However, with the many software packages and methodologies available, it can be difficult to select the most suitable model for the problem at hand without prior knowledge. A promising approach for evaluating the performance of solid-state models is the comparison of the simulations to experimentally measured low-frequency (sub-200 cm-1) vibrational spectra. As this region is dominated by weak intermolecular forces and shallow potential energy surfaces, even slight miscalculations in the solid-state packing arrangements can become readily apparent. In this work, terahertz time-domain spectroscopy and low-frequency Raman spectroscopy are used as benchmark experimental targets to develop computational methodologies for simulating and analyzing the lattice vibrations of molecular crystals such as torsions and translations. The developed computational approaches utilize solid-state density functional theory to account for the periodic nature of a molecular crystal and include careful consideration of the effects that functional choice, basis set composition, and energetic tolerances have on the frequencies and spectral intensities of the sub-200 cm-1 vibrations. These computational methodologies serve as standards for accurately modeling low-frequency vibrations across a range of molecular solids from a small molecule that exhibits unusual thermal behavior to the intricacies of an extensively hydrogen bonded oligopeptide

How do metalloenzymes propagate and control chemical reactions?

Enzymes control and propagate a dizzying array of chemical reactions, including radical reactions and reactions cleaving carbon-carbon bonds. Metalloenzymes, which contain a metal cofactor, are particularly adept at propagating these reactions. This thesis focuses on several metalloenzymes; each an example of a different unique reaction control strategy. Both experimental and computational methodologies have been employed in order to identify specific residues or features which contribute to each enzyme\u27s ability to control the reaction. Emphasis is made on special properties of the metal Manganese. Controlling residues include not only first shell or active site residues, but also residues more distant from the active-site. Further, manipulation of such residues can be used to alter reactivity at non -active-sites, or to alter the apparent electrostatics of the protein (in the case of substitution of hydrogen with fluorine). Electron Paramagnetic Resonance (EPR) and other forms of magnetic spectroscopy can be used to evaluate subtle differences imposed by substitution for controlling residues to a metal center, which gives further insight into the electronic contributions of given residues, as well as the electronic properties of metal cofactors. In summary, the catalysis by Mn-dependent and other metal-dependent metalloenzymes can be investigated through multiple kinetic and spectroscopic avenues, unveiling suprising and novel themes in enzymatic catalysis, such as mechano-chemical switches and super long-distance metallo-interactions

Structure and interaction studies of beta-amyloid in the search for new lead compounds for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is the most devastating neurodegenerative disorder that effects the aging population worldwide. In this study three hypotheses of AD are explored, the β-amyloid cascade hypothesis, the β-amyloid metal binding hypothesis and the oxidative stress hypothesis are explored. In the first case compounds from the South African Natural Compounds Database (SANCDB) are docked to models of β-amyloid fibrils and the properties of these fibrils under pulling simulations are compared to a known small molecule disruptor of β-amyloid, wgx-50. In these simulations SANCDB compounds are identified that disrupt β-amyloid in a similar manner to wgx-50. In these simulations the disruption to the free energy of binding of chains to the fibrils is quantified. For metal binding and oxidative stress hypotheses, problems in simulation arise due to only fragments of β-amyloid being present in the Research Collaboratory for Structural Bioinformatics protein data bank (RCSB PDB), as determined from NMR experiments. In this work, β-amyloid is set up under periodic boundary conditions to simulate a fibril under reasonable computational time. Within these periodic boundary conditions, β-amyloid has been solvated in copper and zinc rich environments and diffusion of these metals around the fibrils has been explored. The localization of these metals (in simulation only using van der Waal’s and electrostatic terms) around the fibril has led us to explore other possible metal binding sites. Metal bound to the infinite fibril has been optimized at the QM/MM level and some of the reactive oxygen species in the presence of the fibril are quantified