Challenges in simulating light-induced processes in DNA

© 2016 by the authors; licensee MDPI, Basel, Switzerland. In this contribution, we give a perspective on the main challenges in performing theoretical simulations of photoinduced phenomena within DNA and its molecular building blocks. We distinguish the different tasks that should be involved in the simulation of a complete DNA strand subject to UV irradiation: (i) stationary quantum chemical computations; (ii) the explicit description of the initial excitation of DNA with light; (iii) modeling the nonadiabatic excited state dynamics; (iv) simulation of the detected experimental observable; and (v) the subsequent analysis of the respective results. We succinctly describe the methods that are currently employed in each of these steps. While for each of them, there are different approaches with different degrees of accuracy, no feasible method exists to tackle all problems at once. Depending on the technique or combination of several ones, it can be problematic to describe the stacking of nucleobases, bond breaking and formation, quantum interferences and tunneling or even simply to characterize the involved wavefunctions. It is therefore argued that more method development and/or the combination of different techniques are urgently required. It is essential also to exercise these new developments in further studies on DNA and subsystems thereof, ideally comprising simulations of all of the different components that occur in the corresponding experiments

Pursuing Excitonic Energy Transfer with Programmable DNA-Based Optical Breadboards

DNA nanotechnology has now enabled the self-assembly of almost any prescribed 3-dimensional nanoscale structure in large numbers and with high fidelity. These structures are also amenable to site-specific modification with a variety of small molecules ranging from drugs to reporter dyes. Beyond obvious application in biotechnology, such DNA structures are being pursued as programmable nanoscale optical breadboards where multiple different/identical fluorophores can be positioned with sub-nanometer resolution in a manner designed to allow them to engage in multistep excitonic energy-transfer (ET) via Förster resonance energy transfer (FRET) or other related processes. Not only is the ability to create such complex optical structures unique, more importantly, the ability to rapidly redesign and prototype almost all structural and optical analogues in a massively parallel format allows for deep insight into the underlying photophysical processes. Dynamic DNA structures further provide the unparalleled capability to reconfigure a DNA scaffold on the fly in situ and thus switch between ET pathways within a given assembly, actively change its properties, and even repeatedly toggle between two states such as on/off. Here, we review progress in developing these composite materials for potential applications that include artificial light harvesting, smart sensors, nanoactuators, optical barcoding, bioprobes, cryptography, computing, charge conversion, and theranostics to even new forms of optical data storage. Along with an introduction into the DNA scaffolding itself, the diverse fluorophores utilized in these structures, their incorporation chemistry, and the photophysical processes they are designed to exploit, we highlight the evolution of DNA architectures implemented in the pursuit of increased transfer efficiency and the key lessons about ET learned from each iteration. We also focus on recent and growing efforts to exploit DNA as a scaffold for assembling molecular dye aggregates that host delocalized excitons as a test bed for creating excitonic circuits and accessing other quantum-like optical phenomena. We conclude with an outlook on what is still required to transition these materials from a research pursuit to application specific prototypes and beyond

Methods used to study the oligomeric structure of G protein-coupled receptors

G-protein coupled receptors (GPCRs), which constitute the largest family of cell surface receptors, were originally thought to function as monomers, but are now recognized as being able to act in a wide range of oligomeric states and indeed, it is known that the oligomerization state of a GPCR can modulate its pharmacology and function. A number of experimental techniques have been devised to study GPCR oligomerization including those based upon traditional biochemistry such as blue-native polyacrylamide gel-electrophoresis (BN-PAGE), co-immunoprecipitation and protein-fragment complementation assays, those based upon resonance energy transfer, fluorescence resonance energy transfer (FRET), time-resolved FRET, FRET spectrometry and bioluminescence resonance energy transfer (BRET). Those based upon microscopy such as fluorescence recovery after photo-bleaching (FRAP), total internal reflection fluorescence microscopy (TIRF), spatial intensity distribution analysis (SpIDA) and various single molecule imaging techniques. Finally with the solution of a growing number of crystal structures, X-ray crystallography must be acknowledged as an important source of discovery in this field. A different, but in many ways complementary approach to the use of more traditional experimental techniques, are those involving computational methods which possess obvious merit in the study of the dynamics of oligomer formation and function. Here we summarize the latest developments which have been made in the methods used to study GPCR oligomerization and give an overview of their application

Composition, thermodynamics, and morphology: A multi-scale computational approach for the design of self-assembling peptides

Peptide self-assembly has generated significant interest as a means for the bottom-up fabrication of highly tunable biocompatible nanoaggregates. Individual peptides can be synthesized to include non-natural π-conjugated subunits, endowing assembled aggregates with a range of optical and electronic properties that render them useful in applications as biocompatible organic electronics. The immense number of possible peptides, however, causes the exhaustive traversal of sequence space to be intractable. This massive composition space lends itself toward the use of computer simulation and data science tools to understand molecular aggregation and guide experimental synthesis and design. In this dissertation, I present work employing a hierarchy of molecular modeling techniques to identify self-assembling peptides with specific photophysical properties by probing thermodynamic and structural characteristics of peptide aggregation. We employ classical molecular dynamics simulation to probe the key molecular forces governing the morphology and free energy of oligomerization, time dependent density functional theory to predict photophysical properties as a function of aggregate morphology, and data-driven quantitative structure property models to perform high-throughput virtual screening of chemical space to identify promising peptide chemistries. This work establishes a multi-scale framework for the principled computational design of self-assembling π-conjugated peptides with engineered photophysical properties

Software for the frontiers of quantum chemistry : An overview of developments in the Q-Chem 5 package

This article summarizes technical advances contained in the fifth major release of the Q-Chem quantum chemistry program package, covering developments since 2015. A comprehensive library of exchange–correlation functionals, along with a suite of correlated many-body methods, continues to be a hallmark of the Q-Chem software. The many-body methods include novel variants of both coupled-cluster and configuration-interaction approaches along with methods based on the algebraic diagrammatic construction and variational reduced density-matrix methods. Methods highlighted in Q-Chem 5 include a suite of tools for modeling core-level spectroscopy, methods for describing metastable resonances, methods for computing vibronic spectra, the nuclear–electronic orbital method, and several different energy decomposition analysis techniques. High-performance capabilities including multithreaded parallelism and support for calculations on graphics processing units are described. Q-Chem boasts a community of well over 100 active academic developers, and the continuing evolution of the software is supported by an “open teamware” model and an increasingly modular design.This article summarizes technical advances contained in the fifth major release of the Q-Chem quantum chemistry program package, covering developments since 2015. A comprehensive library of exchange-correlation functionals, along with a suite of correlated many-body methods, continues to be a hallmark of the Q-Chem software. The many-body methods include novel variants of both coupled-cluster and configuration-interaction approaches along with methods based on the algebraic diagrammatic construction and variational reduced density-matrix methods. Methods highlighted in Q-Chem 5 include a suite of tools for modeling core-level spectroscopy, methods for describing metastable resonances, methods for computing vibronic spectra, the nuclear-electronic orbital method, and several different energy decomposition analysis techniques. High-performance capabilities including multithreaded parallelism and support for calculations on graphics processing units are described. Q-Chem boasts a community of well over 100 active academic developers, and the continuing evolution of the software is supported by an "open teamware" model and an increasingly modular design.Peer reviewe

Computational and Experimental Investigation of Allosteric Communication in the Transcriptional Regulator NikR

The Ni2+ and DNA binding protein NikR is involved in nickel regulation in Escherichia coli through transcriptional repression of the NikABCDE nickel permease. NikR is a homotetramer and each chain contains both a DNA binding ribbon-helix-helix: RHH) domain and a Ni2+ binding regulatory ACT: aspartokinase, chorismate mutase, TyrA) fold. Work herein combines computational modeling of NikR structure with experimental studies aimed at understanding allosteric communication between the ACT and RHH domains. Hydrogen/deuterium exchange mass spectrometry shows a Ni2+ specific NikR conformational change relative to bound Cu2+, Co2+, and Zn2+. Concurrent coordination geometry and in vivo repressor function studies show that NikR activation is specific to binding Ni2+ in square-planar geometry. These results suggest that regions of the NikR structure distal to the Ni2+ binding sites are involved in allosteric communication. To help determine important residue interactions within and between the RHH and ACT domains that are involved in allostery, an equilibrium molecular dynamics: MD) simulation is utilized to explore the conformational dynamics of the NikR tetramer. This study includes advances in methods development focused on identifying signatures of allosteric communication in MD simulations. Using two different correlation measures based on fluctuations in atomic position and non-covalent bonding, we identify a potential allosteric communication pathway between the Ni2+ and DNA binding sites. We also apply a graph theoretic approach to map the most probable networks of non-covalent contacts connecting the two functionally important binding sites. Several of the residues identified by our analyses have been shown experimentally to be important for NikR function. An additional subset of the selected residues structurally connects experimentally important residues and may help coordinate allosteric communication between the ACT and RHH domains. Based on these analyses and additional structural interpretations, site-directed mutagenesis of E. coli NikR and subsequent characterization of changes in Ni2+ binding and in vivo repressor function of mutants aid our understanding of the role of these residues in allosteric regulation. The combination of computational and experimental methods that are developed or adapted in this study provides a framework for further characterization of NikR, other ACT domain containing proteins, and other allosteric proteins

Software for the frontiers of quantum chemistry:An overview of developments in the Q-Chem 5 package

This article summarizes technical advances contained in the fifth major release of the Q-Chem quantum chemistry program package, covering developments since 2015. A comprehensive library of exchange–correlation functionals, along with a suite of correlated many-body methods, continues to be a hallmark of the Q-Chem software. The many-body methods include novel variants of both coupled-cluster and configuration-interaction approaches along with methods based on the algebraic diagrammatic construction and variational reduced density-matrix methods. Methods highlighted in Q-Chem 5 include a suite of tools for modeling core-level spectroscopy, methods for describing metastable resonances, methods for computing vibronic spectra, the nuclear–electronic orbital method, and several different energy decomposition analysis techniques. High-performance capabilities including multithreaded parallelism and support for calculations on graphics processing units are described. Q-Chem boasts a community of well over 100 active academic developers, and the continuing evolution of the software is supported by an “open teamware” model and an increasingly modular design

Software for the frontiers of quantum chemistry: An overview of developments in the Q-Chem 5 package

This article summarizes technical advances contained in the fifth major release of the Q-Chem quantum chemistry program package, covering developments since 2015. A comprehensive library of exchange–correlation functionals, along with a suite of correlated many-body methods, continues to be a hallmark of the Q-Chem software. The many-body methods include novel variants of both coupled-cluster and configuration-interaction approaches along with methods based on the algebraic diagrammatic construction and variational reduced density-matrix methods. Methods highlighted in Q-Chem 5 include a suite of tools for modeling core-level spectroscopy, methods for describing metastable resonances, methods for computing vibronic spectra, the nuclear–electronic orbital method, and several different energy decomposition analysis techniques. High-performance capabilities including multithreaded parallelism and support for calculations on graphics processing units are described. Q-Chem boasts a community of well over 100 active academic developers, and the continuing evolution of the software is supported by an “open teamware” model and an increasingly modular design

Rationally designed substrates for SERS biosensing

Thesis (Ph.D.)--Boston UniversityThe large electromagnetic field enhancement provided by nanostructured noble metal surfaces forms the foundation for a series of enabling optical analytical techniques, such as surface enhanced Raman spectroscopy (SERS), surface enhanced IR absorption spectroscopy (SEIRA), surface enhanced fluorescent microscopy (SEF), to name only a few. Critical sensing applications have, however, other substrate requirements than mere peak signal enhancement. The substrate needs to be reliable, provide reproducible signal enhancements, and be amenable to a combination with microfluidic chips or other integrated sensor platforms. These needs motivate the development of engineerable SERS substrate "chips" with defined near- and far-field responses. In this dissertation, two types of rationally designed SERS substrates - nanoparticle cluster arrays (NCAs) and SERS stamp - will be introduced and characterized. NCAs were fabricated through a newly developed template guided self-assembly fabrication approach, in which chemically synthesized nanoparticles are integrated into predefined patterns using a hybrid top-down/bottom-up approach. Since this method relies on chemically defined building blocks, it can overcome the resolution limit of conventional lithographical methods and facilitates higher structural complexity. NCAs sustain near-field interactions within individual clusters as well as between entire neighboring clusters and create a multi-scale cascaded E-field enhancement throughout the entire array. SERS stamps were generated using an oblique angle metal deposition on a lithographically defined piston. When mounted on a nanopositioning stage, the SERS stamps were enabled to contact biological surfaces with pristine nanostructured metal surfaces for a label-free spectroscopic characterization. The developed engineered substrates were applied and tested in critical sensing applications, including the ultratrace detection of explosive vapors, the rapid discrimination of bacterial pathogens, and the label-free monitoring of the enzymatic degradation of pericellular matrices of cancer cells