Allostery and Conformational Dynamics in cAMP-binding Acyltransferases

Mycobacteria harbor unique proteins that regulate protein lysine acylation in a cAMP-regulated manner. These lysine acyltransferases from Mycobacterium smegmatis (KATms) and Mycobacterium tuberculosis (KATmt) show distinctive biochemical properties in terms of cAMP binding affinity to the N-terminal cyclic nucleotide binding domain and allosteric activation of the C-terminal acyltransferase domain. Here we provide evidence for structural features in KATms that account for high affinity cAMP binding and elevated acyltransferase activity in the absence of cAMP. Structure-guided mutational analysis converted KATms from a cAMP-regulated to a cAMP-dependent acyltransferase and identified a unique asparagine residue in the acyltransferase domain of KATms that assists in the enzymatic reaction in the absence of a highly conserved glutamate residue seen in Gcn5-related N-acetyltransferase-like acyltransferases. Thus, we have identified mechanisms by which properties of similar proteins have diverged in two species of mycobacteria by modifications in amino acid sequence, which can dramatically alter the abundance of conformational states adopted by a protein.

Molecular Dynamics Study of Phonon Screening in Graphene

Phonon interaction with electrons or phonons or with structural defects result in a phonon mode conversion. The mode conversion is governed by the frequency wave-vector dispersion relation. The control over phonon mode or the screening of phonon in graphene is studied using the propagation of amplitude modulated phonon wave-packet. Control over phonon properties like frequency and velocity opens up several wave guiding, energy transport and thermo-electric applications of graphene. One way to achieve this control is with the introduction of nano-structured scattering in the phonon path. Atomistic model of thermal energy transport is developed which is applicable to devices consisting of source, channel and drain parts. Longitudinal acoustic phonon mode is excited from one end of the device. Molecular dynamics based time integration is adopted for the propagation of excited phonon to the other end of the device. The amount of energy transfer is estimated from the relative change of kinetic energy. Increase in the phonon frequency decreases the kinetic energy transmission linearly in the frequency band of interest. Further reduction in transmission is observed with the tuning of channel height of the device by increasing the boundary scattering. Phonon mode selective transmission control have potential application in thermal insulation or thermo-electric application or photo-thermal amplification.

A molecular dynamics study of ambient and high pressure phases of silica: Structure and enthalpy variation with molar volume

Extensive molecular dynamics studies of 13 different silica polymorphs are reported in the isothermal-isobaric ensemble with the Parrinello-Rahman variable shape simulation cell. The van Beest-Kramer-van Santen (BKS) potential is shown to predict lattice parameters for most phases within 2%-3% accuracy, as well as the relative stabilities of different polymorphs in agreement with experiment. Enthalpies of high-density polymorphs - CaCl2-type, alpha-PbO2-type, and pyrite-type for which no experimental data are available as yet, are predicted here. Further, the calculated enthalpies exhibit two distinct regimes as a function of molar volume-for low and medium-density polymorphs, it is almost independent of volume, while for high-pressure phases a steep dependence is seen. A detailed analysis indicates that the increased short-range contributions to enthalpy in the high-density phases arise not only from an increased coordination number of silicon but also shorter Si-O bond lengths. Our results indicate that amorphous phases of silica exhibit better optimization of short-range interactions than crystalline phases at the same density while the magnitude of Coulombic contributions is lower in the amorphous phase. (C) 2014 AIP Publishing LLC.

Local Structural and Environmental Factors Define the Efficiency of an RNA Pseudoknot Involved in Programmed Ribosomal Frameshift Process

In programmed -1 ribosomal frameshift, an RNA pseudoknot stalls the ribosome at specific sequence and restarts translation in a new reading frame. A precise understanding of structural characteristics of these pseudoknots and their PRF inducing ability has not been clear to date. To investigate this phenomenon, we have studied various structural aspects of a -1 PRF inducing RNA pseudoknot from BWYV using extensive molecular dynamics simulations. A set of functional and poorly functional forms, for which previous mutational data were available, were chosen for analysis. These structures differ from each other by either single base substitutions or base-pair replacements from the native structure. We have rationalized how certain mutations in RNA pseudoknot affect its function; e.g., a specific base substitution in loop 2 stabilizes the junction geometry by forming multiple noncanonical hydrogen bonds, leading to a highly rigid structure that could effectively resist ribosome-induced unfolding, thereby increasing efficiency. While, a CG to AU pair substitution in stem 1 leads to loss of noncanonical hydrogen bonds between stems and loop, resulting in a less stable structure and reduced PRF inducing ability, inversion of a pair in stem 2 alters specific base-pair geometry that might be required in ribosomal recognition of nucleobase groups, negatively affecting pseudoknot functioning. These observations illustrate that the ability of an RNA pseudoknot to induce -1 PRF with an optimal rate depends on several independent factors that contribute to either the local conformational variability or geometry

Dynamical facilitation governs glassy dynamics in suspensions of colloidal ellipsoids

One of the greatest challenges in contemporary condensed matter physics is to ascertain whether the formation of glasses from liquids is fundamentally thermodynamic or dynamic in origin. Although the thermodynamic paradigm has dominated theoretical research for decades, the purely kinetic perspective of the dynamical facilitation (DF) theory has attained prominence in recent times. In particular, recent experiments and simulations have highlighted the importance of facilitation using simple model systems composed of spherical particles. However, an overwhelming majority of liquids possess anisotropy in particle shape and interactions, and it is therefore imperative to examine facilitation in complex glass formers. Here, we apply the DF theory to systems with orientational degrees of freedom as well as anisotropic attractive interactions. By analyzing data from experiments on colloidal ellipsoids, we show that facilitation plays a pivotal role in translational as well as orientational relaxation. Furthermore, we demonstrate that the introduction of attractive interactions leads to spatial decoupling of translational and rotational facilitation, which subsequently results in the decoupling of dynamical heterogeneities. Most strikingly, the DF theory can predict the existence of reentrant glass transitions based on the statistics of localized dynamical events, called excitations, whose duration is substantially smaller than the structural relaxation time. Our findings pave the way for systematically testing the DF approach in complex glass formers and also establish the significance of facilitation in governing structural relaxation in supercooled liquids.

Hydrophobic hydration driven self-assembly of curcumin in water: Similarities to nucleation and growth under large metastability, and an analysis of water dynamics at heterogeneous surfaces

As the beneficial effects of curcumin have often been reported to be limited to its small concentrations, we have undertaken a study to find the aggregation properties of curcumin in water by varying the number of monomers. Our molecular dynamics simulation results show that the equilibrated structure is always an aggregated state with remarkable structural rearrangements as we vary the number of curcumin monomers from 4 to 16 monomers. We find that the curcumin monomers form clusters in a very definite pattern where they tend to aggregate both in parallel and anti-parallel orientation of the phenyl rings, often seen in the formation of beta-sheet in proteins. A considerable enhancement in the population of parallel alignments is observed with increasing the system size from 12 to 16 curcumin monomers. Due to the prevalence of such parallel alignment for large system size, a more closely packed cluster is formed with maximum number of hydrophobic contacts. We also follow the pathway of cluster growth, in particular the transition from the initial segregated to the final aggregated state. We find the existence of a metastable structural intermediate involving a number of intermediate-sized clusters dispersed in the solution. We have constructed a free energy landscape of aggregation where the metatsable state has been identified. The course of aggregation bears similarity to nucleation and growth in highly metastable state. The final aggregated form remains stable with the total exclusion of water from its sequestered hydrophobic core. We also investigate water structure near the cluster surface along with their orientation. We find that water molecules form a distorted tetrahedral geometry in the 1st solvation layer of the cluster, interacting rather strongly with the hydrophilic groups at the surface of the curcumin. The dynamics of such quasi-bound water molecules near the surface of curcumin cluster is considerably slower than the bulk signifying a restricted motion as often found in protein hydration layer. (C) 2014 AIP Publishing LLC.

Structure, dynamics and thermodynamics of single-file water under confinement: effects of polarizability of water molecules

Various structural, dynamic and thermodynamic properties of water molecules confined in single-wall carbon nanotubes (CNTs) are investigated using both polarizable and non-polarizable water models. The inclusion of polarizability quantitatively affects the nature of hydrogen bonding, which governs many properties of confined water molecules. Polarizable water leads to tighter hydrogen bonding and makes the distance between neighboring water molecules shorter than that for non-polarizable water. Stronger hydrogen bonding also decreases the rotational entropy and makes the diffusion constant smaller than in TIP3P and TIP3PM water models. The reorientational dynamics of the water molecules is governed by a jump mechanism, the barrier for the jump being highest for the polarizable water model. Our results highlight the role of polarizability in governing the dynamics of confined water and demonstrate that the inclusion of polarizability is necessary to obtain agreement with the results of ab initio simulations for the distributions of waiting and jump times. The SPC/E water model is found to predict various water properties in close agreement with the results of polarizable water models with much lower computational costs.

An overview of recent advances in structural bioinformatics of protein-protein interactions and a guide to their principles

Rich data bearing on the structural and evolutionary principles of protein protein interactions are paving the way to a better understanding of the regulation of function in the cell. This is particularly the case when these interactions are considered in the framework of key pathways. Knowledge of the interactions may provide insights into the mechanisms of crucial `driver' mutations in oncogenesis. They also provide the foundation toward the design of protein protein interfaces and inhibitors that can abrogate their formation or enhance them. The main features to learn from known 3-D structures of protein protein complexes and the extensive literature which analyzes them computationally and experimentally include the interaction details which permit undertaking structure-based drug discovery, the evolution of complexes and their interactions, the consequences of alterations such as post-translational modifications, ligand binding, disease causing mutations, host pathogen interactions, oligomerization, aggregation and the roles of disorder, dynamics, allostery and more to the protein and the cell. This review highlights some of the recent advances in these areas, including design, inhibition and prediction of protein protein complexes. The field is broad, and much work has been carried out in these areas, making it challenging to cover it in its entirety. Much of this is due to the fast increase in the number of molecules whose structures have been determined experimentally and the vast increase in computational power. Here we provide a concise overview. (C) 2014 Elsevier Ltd. All rights reserved.

A transmission electron microscopy and X-ray photoelectron spectroscopy study of annealing induced gamma-phase nucleation, clustering, and interfacial dynamics in reactively sputtered amorphous alumina thin films

Pure alpha-Al2O3 exhibits a very high degree of thermodynamical stability among all metal oxides and forms an inert oxide scale in a range of structural alloys at high temperatures. We report that amorphous Al2O3 thin films sputter deposited over crystalline Si instead show a surprisingly active interface. On annealing, crystallization begins with nuclei of a phase closely resembling gamma-Alumina forming almost randomly in an amorphous matrix, and with increasing frequency near the substrate/film interface. This nucleation is marked by the signature appearance of sharp (400) and (440) reflections and the formation of a diffuse diffraction halo with an outer maximal radius of approximate to 0.23 nm enveloping the direct beam. The microstructure then evolves by a cluster-coalescence growth mechanism suggestive of swift nucleation and sluggish diffusional kinetics, while locally the Al ions redistribute slowly from chemisorbed and tetrahedral sites to higher anion coordinated sites. Chemical state plots constructed from XPS data and simple calculations of the diffraction patterns from hypothetically distorted lattices suggest that the true origins of the diffuse diffraction halo are probably related to a complex change in the electronic structure spurred by the a-gamma transformation rather than pure structural disorder. Concurrent to crystallization within the film, a substantially thick interfacial reaction zone also builds up at the film/substrate interface with the excess Al acting as a cationic source. (C) 2015 AIP Publishing LLC.

Mode coupling theory analysis of electrolyte solutions: Time dependent diffusion, intermediate scattering function, and ion solvation dynamics

A self-consistent mode coupling theory (MCT) with microscopic inputs of equilibrium pair correlation functions is developed to analyze electrolyte dynamics. We apply the theory to calculate concentration dependence of (i) time dependent ion diffusion, (ii) intermediate scattering function of the constituent ions, and (iii) ion solvation dynamics in electrolyte solution. Brownian dynamics with implicit water molecules and molecular dynamics method with explicit water are used to check the theoretical predictions. The time dependence of ionic self-diffusion coefficient and the corresponding intermediate scattering function evaluated from our MCT approach show quantitative agreement with early experimental and present Brownian dynamic simulation results. With increasing concentration, the dispersion of electrolyte friction is found to occur at increasingly higher frequency, due to the faster relaxation of the ion atmosphere. The wave number dependence of intermediate scattering function, F(k, t), exhibits markedly different relaxation dynamics at different length scales. At small wave numbers, we find the emergence of a step-like relaxation, indicating the presence of both fast and slow time scales in the system. Such behavior allows an intriguing analogy with temperature dependent relaxation dynamics of supercooled liquids. We find that solvation dynamics of a tagged ion exhibits a power law decay at long times-the decay can also be fitted to a stretched exponential form. The emergence of the power law in solvation dynamics has been tested by carrying out long Brownian dynamics simulations with varying ionic concentrations. The solvation time correlation and ion-ion intermediate scattering function indeed exhibit highly interesting, non-trivial dynamical behavior at intermediate to longer times that require further experimental and theoretical studies. (c) 2015 AIP Publishing LLC.

Composition dependent multiple structural transformations of myoglobin in aqueous ethanol solution: A combined experimental and theoretical study

Experimental studies (circular dichroism and ultra-violet (UV) absorption spectra) and large scale atomistic molecular dynamics simulations (accompanied by order parameter analyses) are combined to establish a number of remarkable (and unforeseen) structural transformations of protein myoglobin in aqueous ethanol mixture at various ethanol concentrations. The following results are particularly striking. (1) Two well-defined structural regimes, one at x(EtOH) similar to 0.05 and the other at x(EtOH) similar to 0.25, characterized by formation of distinct partially folded conformations and separated by a unique partially unfolded intermediate state at x(EtOH) similar to 0.15, are identified. (2) Existence of non-monotonic composition dependence of (i) radius of gyration, (ii) long range contact order, (iii) residue specific solvent accessible surface area of tryptophan, and (iv) circular dichroism spectra and UV-absorption peaks are observed. Interestingly at x(EtOH) similar to 0.15, time averaged value of the contact order parameter of the protein reaches a minimum, implying that this conformational state can be identified as a molten globule state. Multiple structural transformations well known in water-ethanol binary mixture appear to have considerably stronger effects on conformation and dynamics of the protein. We compare the present results with studies in water-dimethyl sulfoxide mixture where also distinct structural transformations are observed along with variation of co-solvent composition. (C) 2015 AIP Publishing LLC.

Catalytic pathway, substrate binding and stability in SAICAR synthetase: A structure and molecular dynamics study

The de novo purine biosynthesis is one of the highly conserved pathways among all organisms and is essential for the cell viability. A clear understanding of the enzymes in this pathway would pave way for the development of antimicrobial and anticancer drugs. Phosphoribosylaminoimidazole-succinocar boxamide (SAICAR) synthetase is one of the enzymes in this pathway that catalyzes ATP dependent ligation of carboxyaminoimidazole ribotide (CAIR) with L-aspartate (ASP). Here, we describe eight crystal structures of this enzyme, in C222(1) and H3 space groups, bound to various substrates and substrate mimics from a hyperthermophilic archaea Pyrococcus horikoshii along with molecular dynamics simulations of the structures with substrates. Complexes exhibit minimal deviation from its apo structure. The CAIR binding site displays a preference for pyrimidine nucleotides. In the ADP.TMP-ASP complex, the ASP binds at a position equivalent to that found in Saccharomyces cerevisiae structure (PDB: 2CNU) and thus, clears the ambiguity regarding ASP's position. A possible mode for the inhibition of the enzyme by CTP and UTP, observed earlier in the yeast enzyme, is clearly illustrated in the structures bound to CMP and UMP. The ADP.Mg2+.PO4.CD/MP complex having a phosphate ion between the ATP and CAIR sites strengthens one of the two probable pathways (proposed in Escherichia coli study) of catalytic mechanism and suggests the possibility of a phosphorylation taking place before the ASP's attack on CAIR. Molecular dynamic simulations of this enzyme along with its substrates at 90 degrees C reveal the relative strengths of substrate binding, possible antagonism and the role of Mg2+ ions. (C) 2015 Elsevier Inc. All rights reserved.

Impact of glycosylation on stability, structure and unfolding of soybean agglutinin (SBA): an insight from thermal perturbation molecular dynamics simulations

Glycosylation has been recognized as one of the most prevalent and complex post-translational modifications of proteins involving numerous enzymes and substrates. Its effect on the protein conformational transitions is not clearly understood yet. In this study, we have examined the effect of glycosylation on protein stability using molecular dynamics simulation of legume lectin soybean agglutinin (SBA). Its glycosylated moiety consists of high mannose type N-linked glycan (Man(9)GlcNAc(2)). To unveil the structural perturbations during thermal unfolding of these two forms, we have studied and compared them to the experimental results. From the perspective of dynamics, our simulations revealed that the nonglycosylated monomeric form is less stable than corresponding glycosylated form at normal and elevated temperatures. Moreover, at elevated temperature thermal destabilization is more prominent in solvent exposed loops, turns and ends of distinct beta sheets. SBA maintains it folded structure due to some important saltbridges, hydrogen bonds and hydrophobic interactions within the protein. The reducing terminal GlcNAc residues interact with the protein residues VAL161, PRO182 and SER225 via hydrophobic and via hydrogen bonding with ASN 9 and ASN 75. Our simulations also revealed that single glycosylation (ASN75) has no significant effect on corresponding cis peptide angle orientation. This atomistic description might have important implications for understanding the functionality and stability of Soybean agglutinin.

Dynamics of history-dependent epidemics in temporal networks

The structural properties of temporal networks often influence the dynamical processes that occur on these networks, e.g., bursty interaction patterns have been shown to slow down epidemics. In this paper, we investigate the effect of link lifetimes on the spread of history-dependent epidemics. We formulate an analytically tractable activity-driven temporal network model that explicitly incorporates link lifetimes. For Markovian link lifetimes, we use mean-field analysis for computing the epidemic threshold, while the effect of non-Markovian link lifetimes is studied using simulations. Furthermore, we also study the effect of negative correlation between the number of links spawned by an individual and the lifetimes of those links. Such negative correlations may arise due to the finite cognitive capacity of the individuals. Our investigations reveal that heavy-tailed link lifetimes slow down the epidemic, while negative correlations can reduce epidemic prevalence. We believe that our results help shed light on the role of link lifetimes in modulating diffusion processes on temporal networks.

Influence of a Counterion on the Ion Atmosphere of an Anion: A Molecular Dynamics Study of LiX and CsX (X = F-, Cl-, I-) in Methanol

We report molecular dynamics (MD) simulations to explore the influence of a counterion on the structure and dynamics of cationic and anionic solvation shells for various ions in methanol at 298 K. We show that the variation in ionic size of either the cation or the anion in an ion pair influences the solvation structure of the other ion as well as the diffusivity in an electrolyte solution of methanol. The extent of ionic association between the cation and its counteranion of different ionic sizes has been investigated by analyzing the radial distribution functions (RDFs) and the orientation of methanol molecules in the first solvation shell (FSS) of ions. It is shown that the methanol in the FSS of the anion as well the cation exhibit quite different radial and orientational structures as compared to methanol which lie in the FSS of either the anion or the cation but not both. We find that the coordination number (CN) of F-, Cr-, and I- ions decreases with increasing size of the anion which is contrary to the trend reported for the anions in H2O. The mean residence time (MRT) of methanol molecules in the FSS of ions has been calculated using the stable states picture (SSP) approach. It is seen that the ion-counterion interaction has a considerable influence on the MRT of methanol molecules in the FSS of ions. We also discuss the stability order of the ion-counterion using the potentials of mean force (PMFs) for ion pairs with ions of different sizes. The PMF plots reveal that the Li+-F- pair (small-small) is highly stable and the Li+-I- pair is least stable (small-large) in electrolyte solutions.