Terahertz dielectric study of bio-molecules using time-domain spectrometry and molecular dynamics simulations

PhDTerahertz frequency domain constitutes the least explored part of electromagnetic spectrum. At the same time plenty of physical phenomena occurs on picoseconds to nanosecond time-scale and have and can be monitored/controlled/studied by THz and sub-THz waves. Since the advent of photo-conductive generation followed by invention of the first THz-TDS system, research in this field made a huge progress, although still possess a considerable potential for growth. Alongside advances in generation and detection of THz radiation simulation tools are becoming increasingly important and facilitate interpretation of the experimental results. Thesis comprises three related subjects, namely the processing of THz-TDS raw data, analysis of protein solvation dynamics by simulations and experimental investigation of water-protein solution at different concentrations. Experimental works in this thesis is performed using THz-TDS (normally covers 0.1-4 THz domain) and quasi-optical bench which covers the 75-325 GHz frequency bands. Molecular dynamics simulations were conducted in Gromacs package with a purely mechanical force field. The thesis is organized in the following way: chapter 1 introduces THz frequency domain to the reader, by describing its location in the electromagnetic spectrum, the physical phenomena that falls to THz domain, the main applications of THz radiation and overview of the mechanism of interaction between THz waves and bio-molecules. Second chapter outlines the principles of operation, physical processes and areas of application of THz-TDS. It is completed with a detailed description of the THz-TDS available in our laboratory. Third chapter gives a general picture of data processing related to material parameter extraction from time-domain response of the sample recorded by THz-TDS. Then it goes into details of associated error analysis, introducing the uncertainty caused by utilization of approximated transfer function. The application of the accurate algorithm for sample thickness determination based on its THz response is also presented in the third chapter. The fourth chapter discusses the application of Gromacs molecular dynamics simulations for the study of solvation dynamics of four selected proteins, namely TRP-tail, TRP-cage, BPTI and lysozyme proteins. All the water molecules solvating protein are divided into buried in the protein interior structure and the ‘on-surface’ water molecules. The later is shown to have similar properties for all proteins, while the former serve as the origin for the differences in solvation dynamics of proteins. Further in this chapter the radius of hydration shell and its dependence on the protein structure is investigated using vibrational density of states of solvating water molecules. The experimental investigation of the lysozyme, myoglobin and BSA proteins solutions performed over 0.22-0.325 THz domain using the PNA-driven quasi-optical bench is described in chapter 5. The relative absorption of protein molecules in solution and the hydration shell depth is also estimated. The last chapter concludes the thesis and outlines some future prospects.Queen Mary University of London College Doctoral Training fund (now – Principal’s studentship

Argonne National Laboratory annual report of laboratory directed research and development program activities for FY 1995.

The purposes of Argonne's Laboratory Directed Research and Development (LDRD) Program are to encourage the development of novel concepts, enhance the Laboratory's R&D capabilities, and further the development of its strategic initiatives

Graphics Processing Unit Accelerated Coarse-Grained Protein-Protein Docking

Graphics processing unit (GPU) architectures are increasingly used for general purpose computing, providing the means to migrate algorithms from the SISD paradigm, synonymous with CPU architectures, to the SIMD paradigm. Generally programmable commodity multi-core hardware can result in significant speed-ups for migrated codes. Because of their computational complexity, molecular simulations in particular stand to benefit from GPU acceleration. Coarse-grained molecular models provide reduced complexity when compared to the traditional, computationally expensive, all-atom models. However, while coarse-grained models are much less computationally expensive than the all-atom approach, the pairwise energy calculations required at each iteration of the algorithm continue to cause a computational bottleneck for a serial implementation. In this work, we describe a GPU implementation of the Kim-Hummer coarse-grained model for protein docking simulations, using a Replica Exchange Monte-Carlo (REMC) method. Our highly parallel implementation vastly increases the size- and time scales accessible to molecular simulation. We describe in detail the complex process of migrating the algorithm to a GPU as well as the effect of various GPU approaches and optimisations on algorithm speed-up. Our benchmarking and profiling shows that the GPU implementation scales very favourably compared to a CPU implementation. Small reference simulations benefit from a modest speedup of between 4 to 10 times. However, large simulations, containing many thousands of residues, benefit from asynchronous GPU acceleration to a far greater degree and exhibit speed-ups of up to 1400 times. We demonstrate the utility of our system on some model problems. We investigate the effects of macromolecular crowding, using a repulsive crowder model, finding our results to agree with those predicted by scaled particle theory. We also perform initial studies into the simulation of viral capsids assembly, demonstrating the crude assembly of capsid pieces into a small fragment. This is the first implementation of REMC docking on a GPU, and the effectuate speed-ups alter the tractability of large scale simulations: simulations that otherwise require months or years can be performed in days or weeks using a GPU

Investigation of Heterogeneous Proteins and Protein Complexes with Native Ion Mobility-Mass Spectrometry and Theory

Native ion mobility-mass spectrometry (IM-MS) offers many advantages for the study of biomolecules and their complexes. High mass accuracy and sensitivity enable unambiguous determination of complex stoichiometries with respect to subunit composition as well as bound ligands. Ion mobility spectrometry adds an additional dimension of separation and can provide some structural information. Native IM-MS experiments are also fast with minimal sample requirements. Because of these reasons, native IM-MS has become an important tool in structural biology, able to investigate challenging samples that may not be amenable to study by other techniques. However, there are still some major challenges for using native IM-MS in the study of biomolecules. Heterogeneity—arising from the presence of multiple conformations, subunit compositions, ligands and small molecules, for example—results in complicated native mass spectra that can be difficult or even impossible to deconvolute and interpret. Characterizing the heterogeneity of these samples is desirable, as reports of lipids, small drugs, and metals being important for physiological structure and function continue to accumulate. Additionally, interpretation of structural information from IM data has remained largely qualitative, and more fundamental questions about this technique persist, including detailed understanding of the nature of gas-phase protein structure and behavior and how it might differ from solution-phase. Investigation into this aspect is required to make structural interpretation from native IM-MS data quantitative. In the first half of this dissertation, strategies to overcome the challenges of heterogeneity are explored, and computational methods are developed to solve the quantitation problem. With these methods, key features of gas-phase protein ion compaction are revealed, allowing more informed interpretation of structural details from this technique. The second half of this dissertation illustrates the wealth of information that can be accessed for challenging, heterogeneous biomolecules in native IM-MS experiments upon application of these computational methods. With results from both experiment and computation, oligomeric states of the membrane pore-forming protein toxin Cytolysin A are identified, and the composition and topology of multimeric β-crystallin protein complexes, which are implicated in cataract formation, are characterized. This dissertation includes previously published and unpublished co-authored material

58th Annual Rocky Mountain Conference on Magnetic Resonance

Final program, abstracts, and information about the 58th annual meeting of the Rocky Mountain Conference on Magnetic Resonance, co-endorsed by the Colorado Section of the American Chemical Society and the Society for Applied Spectroscopy. Held in Breckenridge, Colorado, July 17-21, 2016