Conformations and coherences in structure determination by ultrafast electron diffraction

In this article we consider consequences of spatial coherences and conformations in diffraction of (macro)molecules with different potential energy landscapes. The emphasis is on using this understanding to extract structural and temporal information from diffraction experiments. The theoretical analysis of structural interconversions spans an increased range of complexity, from small hydrocarbons to proteins. For each molecule considered, we construct the potential energy landscape and assess the characteristic conformational states available. For molecules that are quasiharmonic in the vicinity of energy minima, we find that the distinct conformer model is sufficient even at high temperatures. If, however, the energy surface is either locally flat around the minima or the molecule includes many degrees of conformational freedom, a Boltzmann ensemble must be used, in what we define as the pseudoconformer approach, to reproduce the diffraction. For macromolecules with numerous energy minima, the ensemble of hundreds of structures is considered, but we also utilize the concept of the persistence length to provide information on orientational coherence and its use to assess the degree of resonance contribution to diffraction. It is shown that the erosion of the resonant features in diffraction which are characteristic of some quasiperiodic structural motifs can be exploited in experimental studies of conformational interconversions triggered by a laser-induced temperature jump

Complexity, Emergent Systems and Complex Biological Systems:\ud Complex Systems Theory and Biodynamics. [Edited book by I.C. Baianu, with listed contributors (2011)]

An overview is presented of System dynamics, the study of the behaviour of complex systems, Dynamical system in mathematics Dynamic programming in computer science and control theory, Complex systems biology, Neurodynamics and Psychodynamics.\u

Basic Atomic Physics

Contains reports on five research projects.Joint Services Electronics Program Contract DAAL03-92-C-0001Joint Services Electronics Program Grant DAAH04-95-1-0038National Science Foundation Grant PHY 92-21489U.S. Navy - Office of Naval Research Grant N00014-90-J-1322National Science Foundation Grant PHY 92-22768U.S. Army - Office of Scientific Research Grant DAAL03-92-G-0229U.S. Army - Office of Scientific Research Grant DAAL01-92-6-0197U.S. Navy - Office of Naval Research Grant N00014-89-J-1207Alfred P. Sloan FoundationU.S. Navy - Office of Naval Research Grant N00014-90-J-1642U.S. Navy - Office of Naval Research Grant N00014-94-1-080

Discovery of Potent Tyrosyl-DNA Phosphodiesterase 1 Inhibitors Using in silico Virtual Screening & Network Analysis for Evolution of Allosteric Communication in 3-ketosteroid Receptors

Tyrosyl-DNA phosphodiesterase I (TDP1) plays an important role in repair of topoisomerase I-DNA complexes in vivo, and its inhibitors have the potential to enhance the efficacy of the Top1-targeting drugs in anticancer therapy. Nevertheless a large number of TDP1 inhibitors have been reported, none of them has inhibition activity in vivo. We present a virtual screening protocol to explore potent TDP1-selective inhibitors. 3-ketosteroid receptors belong to nuclear receptor family, and their DNA binding domains interact with glucocorticoid response elements (GREs) to regulate gene transcription. With evolution, all of them can bind to activating response element ((+)GRE), but only some exhibit the ability to bind to negative glucocorticoid response element (nGRE). It was found that evolutionary mutations are important to change their binding functions. We have presented dynamic network models to elucidate allosteric communication for selected evolutionary homologues, discussing the correlation between binding characteristics and epistatic mutations from network theory

Interdependence, Reflexivity, Fidelity, Impedance Matching, and the Evolution of Genetic Coding

Genetic coding is generally thought to have required ribozymes whose functions were taken over by polypeptide aminoacyl-tRNA synthetases (aaRS). Two discoveries about aaRS and their interactions with tRNA substrates now furnish a unifying rationale for the opposite conclusion: that the key processes of the Central Dogma of molecular biology emerged simultaneously and naturally from simple origins in a peptide•RNA partnership, eliminating the epistemological utility of a prior RNA world. First, the two aaRS classes likely arose from opposite strands of the same ancestral gene, implying a simple genetic alphabet. The resulting inversion symmetries in aaRS structural biology would have stabilized the initial and subsequent differentiation of coding specificities, rapidly promoting diversity in the proteome. Second, amino acid physical chemistry maps onto tRNA identity elements, establishing reflexive, nanoenvironmental sensing in protein aaRS. Bootstrapping of increasingly detailed coding is thus intrinsic to polypeptide aaRS, but impossible in an RNA world. These notions underline the following concepts that contradict gradual replacement of ribozymal aaRS by polypeptide aaRS: (i) aaRS enzymes must be interdependent; (ii) reflexivity intrinsic to polypeptide aaRS production dynamics promotes bootstrapping; (iii) takeover of RNA-catalyzed aminoacylation by enzymes will necessarily degrade specificity; (iv) the Central Dogma's emergence is most probable when replication and translation error rates remain comparable. These characteristics are necessary and sufficient for the essentially de novo emergence of a coupled gene-replicase-translatase system of genetic coding that would have continuously preserved the functional meaning of genetically encoded protein genes whose phylogenetic relationships match those observed today

Spectroscopic Probes of Low-Barrier Proton-Transfer Dynamics

The diverse discipline of molecular spectroscopy, which has profited tremendously from the advent of tunable laser sources, has transformed the scientific community’s knowledge of the microscopic world, allowing the study of perplexing quantum-chemical phenomena. Classically-hindered proton transfer, a multidimensional process mediated by nuclear-quantum effects (e.g., potential-barrier tunneling), is a chemical transformation that forms the crux of all acid/base chemistry. Although extensive research efforts have aimed to establish the paradigms that govern this transformation, a full understanding has proven elusive with questions continuing to emerge.Exploring the proton-transfer reaction, and the related concept of hydrogen bonding, has benefitted greatly from investigations of model systems where the hydron migration is facilitated by a symmetric double-minimum potential well. In such molecular species, the spectroscopic signature of tunneling-induced bifurcations gives a direct measure of reaction rates, thus enabling the extraction of dynamical information. This thesis focuses on a relatively unexplored member of this group, 6-hydroxy-2- formylfulvene or HFF, which exhibits a quasi-linear reaction site on a conjugated framework – a structural arrangement that engenders a low-barrier hydrogen bonding (LBHBing) motif. Additionally, HFF has been suggested to experience a drastic quenching in dynamics accompanying π*←π electronic excitation that has been attributed to a substantial change in reaction mechanism whereby the strictly planar reaction coordinate in the X1A1 state transforms into an out-of-plane pathway involving substantial heavy- atom motion in the A1B2 (π∗π) state. The unique structural and dynamical characteristics of HFF create a potent platform for studying the effects of isotopic substitution and vibrational excitation on tunneling phenomena as presented in this thesis. The origin band of HFF and its monodeuterated isotopolog, HFF-d, were probed using polarization-resolved degenerate four-wave mixing (DFWM), an absorption-based technique that provides near-rotational resolution. This enabled the measurement of tunneling-induced bifurcations for the vibrationless A1B2 states of HFF and HFF-d, yielding Δ = 0.1009(43) cm-1 and Δ = 0.074(10) cm-1, respectively. These values imply a small deuterium kinetic isotope effect (DKIE) of Λ = 1.36 (relative to the analogous ground-state value of Λ = 3.44) that can be rationalized by considering the substantial heavy-atom motion (and the corresponding large effective mass) that is involved in the excited-state proton-transfer process, which dominates the reaction and makes the change in the mass of the shuttling hydron less consequential. Similar DFWM studies also were performed for two higher-energy vibronic bands of A1B2 (π∗π) HFF and HFF-d, ν4(a1), a chelate-ring breathing mode, and ν7(b2), a chelate-ring deformation mode. Although vibrational excitation can have a substantial effect on proton-transfer dynamics, the two studied modes did not couple effectively to the reaction coordinate and, therefore, resulted in minimal changes to measured tunneling splittings, thereby highlighting the distinct nature of the multidimensional out-of-plane tunneling mechanism that governs the π * ← π excited state