PubMed Health⌕ Search

Biomedical subjects

R Stephen Berry

Publications and source records attributed to R Stephen Berry.

At least 19 recordsLinked to original sources
PubMed2006

Characterizing potential surface topographies through the distribution of saddles and minima.

Three related clusters of thirteen particles bound by pairwise Morse potentials with different ranges are the vehicles for relating the dynamics and kinetics of these clusters to the topographies of their energy landscapes. The analyses are based on the distributions of minima and saddles, on the asymmetries of the barriers and the kinetics of passage among the energy bands that the distributions of minima display. While all three of the examples are essentially structure-seekers, the extent of this character is clearly related to the range of the potential.

Journal Article↗
PubMed2006

The origin of long-range attraction between hydrophobes in water.

When water-coated hydrophobic surfaces meet, direct contacts form between the surfaces, driving water out. However, long-range attractive forces first bring those surfaces close. This analysis reveals the source and strength of the long-range attraction between water-coated hydrophobic surfaces. The origin is in the polarization field produced by the strong correlation and coupling of the dipoles of the water molecules at the surfaces. We show that this polarization field gives rise to dipoles on the surface of the hydrophobic solutes that generate long-range hydrophobic attractions. Thus, hydrophobic aggregation begins with a step in which water-coated nonpolar solutes approach one another due to long-range electrostatic forces. This precursor regime occurs before the entropy increase of releasing the water layers and the short-range van der Waals attraction provide the driving force to "dry out" the contact surface. The effective force of attraction is derived from basic molecular principles, without assumptions of the structure of the hydrophobe-water interaction. The strength of this force can be measured directly from atomic force microscopy images of a hydrophobic molecule tethered to a surface but extending into water, and another hydrophobe attached to an atomic force probe. The phenomenon can be observed in the transverse relaxation rates in water proton magnetic resonance as well. The results shed light on the way water mediates chemical and biological self-assembly, a long outstanding problem.

Biopolymers↗
PubMed2006

Minimalist representations and the importance of nearest neighbor effects in protein folding simulations.

In order to investigate the level of representation required to simulate folding and predict structure, we test the ability of a variety of reduced representations to identify native states in decoy libraries and to recover the native structure given the advanced knowledge of the very broad native Ramachandran basin assignments. Simplifications include the removal of the entire side-chain or the retention of only the Cbeta atoms. Scoring functions are derived from an all-atom statistical potential that distinguishes between atoms and different residue types. Structures are obtained by minimizing the scoring function with a computationally rapid simulated annealing algorithm. Results are compared for simulations in which backbone conformations are sampled from a Protein Data Bank-based backbone rotamer library generated by either ignoring or including a dependence on the identity and conformation of the neighboring residues. Only when the Cbeta atoms and nearest neighbor effects are included do the lowest energy structures generally fall within 4 A of the native backbone root-mean square deviation (RMSD), despite the initial configuration being highly expanded with an average RMSD > or = 10 A. The side-chains are reinserted into the Cbeta models with minimal steric clash. Therefore, the detailed, all-atom information lost in descending to a Cbeta-level representation is recaptured to a large measure using backbone dihedral angle sampling that includes nearest neighbor effects and an appropriate scoring function.

Amino Acids↗
PubMed2006

Ultrafast dynamics in atomic clusters: analysis and control.

We present a study of dynamics and ultrafast observables in the frame of pump-probe negative-to-neutral-to-positive ion (NeNePo) spectroscopy illustrated by the examples of bimetallic trimers Ag2Au-/Ag2Au/Ag2Au+ and silver oxides Ag3O2-/Ag3O2/Ag3O2+ in the context of cluster reactivity. First principle multistate adiabatic dynamics allows us to determine time scales of different ultrafast processes and conditions under which these processes can be experimentally observed. Furthermore, we present a strategy for optimal pump-dump control in complex systems based on the ab initio Wigner distribution approach and apply it to tailor laser fields for selective control of the isomerization process in Na3F2. The shapes of pulses can be assigned to underlying processes, and therefore control can be used as a tool for analysis.

Journal Article↗
PubMed2005

Packing defects as selectivity switches for drug-based protein inhibitors.

The conservation of structure across homolog proteins often diffuses the impact of drug-based inhibition by promoting alternative protein-ligand associations that may lead to toxic side effects. However, sticky packing defects are typically not conserved across homologs, making them valuable a priori targets to enhance specificity. By introducing a homology to quantify packing differences among proteins, we enable a previously undescribed strategy for the design of highly selective drug inhibitors involving ligands that wrap nonconserved packing defects. The selectivity of these ligands is validated by performing affinity assays on a cancer-related pharmacokinome. Minor reengineering of a powerful inhibitor guided by wrapping differences across its target kinome can selectively direct its impact toward a specific kinase. Thus, nonconserved packing defects may be used as selectivity switches across homolog targets, using spatial displacements of packing defects across aligned protein structures.

Drug Design↗
PubMed2005

Time autocorrelation function analysis of master equation and its application to atomic clusters.

We derive the energy fluctuation Delta(2)E, and the time autocorrelation kappa(tau) and its Fourier transformation--the fluctuation spectra S(omega)--of the master-equation transition matrix. The contribution from each eigenmode of the transition matrix to these fluctuation quantities reveals the relevant importance of the individual mode in the relaxation processes. The time scales associated with these relaxation processes are determined by the corresponding eigenvalues. Unlike traditional time evolution analysis, the autocorrelation function and fluctuation spectra analysis does not involve an arbitrary initial population. It is also more suitable for analyzing the underlying dynamic, kinetic behavior near the equilibrium and the behavior of the long-time-scale rare events. We utilize our technique to analyze the solid-liquid phase coexistence of the 13-atom Morse cluster and the fcc-to-icosahedral structure transition of the 38-atom Lennard-Jones cluster. For the processes studied, the fluctuation spectra from the master equation simplify the analysis of the transition matrix, and the important relaxation modes are easily extracted.

Chemistry, Physical↗
PubMed2005

Kinetics of model energy landscapes: an approach to complex systems.

An idealized potential energy surface (PES), simply a PES-like network of stationary points, is demonstrated to be a useful tool to study kinetic relaxation of complex energy landscapes. Combined with a master equation, we show that if constructed with proper regularity, the kinetics of the PES is easy to predict and understand by carefully examining the eigenmodes of the master equation. By modifying the idealized PES model to make it more and more complicated, we demonstrate a systematic method to study the complex kinetics on large PES. The idealized PES model is used to explore the feasibility and the robustness of statistical sampling of large PES. We develop several sampling strategies, such as the "rough topography sampling" and the "low barrier saddle sampling" in the idealized PES model and find they are also applicable to a realistic PES of the 13-atom Morse cluster with range parameter rho= 6. To measure the robustness of the sampling methods, we compare the eigenvalue spectra, the eigenvector similarity and the relaxation times of the total energy of the full and sample PESs.

Algorithms↗
PubMed2005

Visualization of electron correlation in autoionizing states above the 3p threshold in magnesium.

The conditional probability density has been calculated for a number of autoionizing states (AIS) in Mg above the 3p threshold. The correlation in such high energy AIS has not been extensively studied and provides insight into the rovibrator behavior of two-electron atoms. The calculations have been done by configuration interaction (CI) with a B-spline basis. This allows for the simultaneous study of the effects of electron correlation and the widths and angular distribution of photoelectrons in multiphoton ionization. The states have been assigned approximate vibrational quantum numbers, and a correlation between the approximate quantum numbers and the photoelectron distribution is observed. Probability distribution for one electron when the other, represented by the small spike, is at its most probable distance from the nucleus. This is a distribution for the doubly-excited 1S(e) state commonly labeled as the 4s2 state.

Algorithms↗
PubMed2005

Archetypal energy landscapes: dynamical diagnosis.

Recent studies have identified several motifs for potential energy surfaces corresponding to distinct dynamic and thermodynamic properties. The corresponding disconnectivity graphs were identified as "palm tree," "willow tree," and "banyan tree" patterns. In the present contribution we present a quantitative analysis of the relation between the topography and dynamics for each of these motifs. For the palm tree and willow tree forms we find that the arrangement of the stationary points in the monotonic sequences with respect to the global minimum is the most important factor in establishing the kinetic properties. However, the results are somewhat different for motifs involving a rough surface with several deep basins (banyan tree motif), with large barriers relative to the energy differences between minima. Here it is the size of the barrier for escape from the region relative to the barriers at the bottom that is most important. The present results may be helpful in distinguishing between the dynamics of "structure seeking" and "glass forming" systems.

Journal Article↗
PubMed2005

The physics of the interactions governing folding and association of proteins.

The review discusses the molecular origins of the forces and free energies that determine several things about proteins, and how experiment and theory reveal this information. The first subject is the stability of the folded, native structures. The second is the range of molecular mechanisms by which proteins find their way to those folded structures in laboratory environments. The third is the much more complex problem of how folding occurs in the cellular environment. This topic includes a discussion of crowding and of the roles of chaperone molecules. The review concludes with a discussion of protein aggregation and fibril formation and of misfolding and therapies associated with it.

Amino Acids↗
PubMed2004

Dielectric modulation of biological water.

We show that water constrained by vicinal hydrophobes undergoes a librational dynamics that lowers the dielectric susceptibility and induces a "redshift" of the relaxation frequency in the hydration shell. The results shed light on the way proteins enhance their intramolecular interactions as they fold or associate.

Body Water↗
PubMed2004

Molecular dimension explored in evolution to promote proteomic complexity.

The architecture of present-day protein interaction networks depends on how protein associations evolved. Here, we explore how and why evolution-related mutations influence protein structure to promote protein associations, and thereby network development. We specifically address two questions: (i) How can protein folds remain conserved while proteins accommodate new binding partnerships as genes duplicate? (ii) What is the structural/molecular basis for hub proteins being the most likely to acquire new connections? The answers stem from the examination of the structure wrapping, or protection from water attack. Wrapping is shown to be a crucial consideration in the exploration and evolution of proteomic interactivity.

Evolution, Molecular↗
PubMed2004

How much can an intermediate state influence competing reactive pathways?

A molecule undergoing reaction may form a short-lived intermediate. Under certain conditions, the rate at which the reaction proceeds toward the product state via the intermediate may exceed that of a simple, direct path. The competition of two alternative reactive pathways is analyzed here in terms of a stochastic model. The approach allows one to diagnose this competition as a function of the energy of the intermediate relative to the barrier heights of the potential surface and values of the reactive vibrational modes. The result has applications to a variety of problems in chemical physics, ranging from the "lock-and-key" mechanism for the enzymatic activity to control of temporal evolution of complex systems by optimal laser fields.

Journal Article↗
PubMed2004

The nonconserved wrapping of conserved protein folds reveals a trend toward increasing connectivity in proteomic networks.

Although protein folding domains are generally conserved for function across distant homologous sequences, one crucial structural feature is not conserved: the wrapping of backbone hydrogen bonds, that is, the extent to which they are intramolecularly desolvated and thereby protected from water attack. Extensive data on protein complex interfaces led us to postulate that insufficiently wrapped backbone hydrogen bonds in monomeric domains must be adhesive, and therefore determinants of interactivity, a result that has been experimentally confirmed. Here, we show that the wrapping of certain conserved folds becomes progressively poorer as species diverge in some lineages. This trend is thus concurrent with a progressive enhancement of the interactivity of individual domains sharing the conserved fold. Such increase in interactivity is predicted to impose an "evolutionary brake" on the overall speed of sequence divergence. This phenomenon follows when more and more residues become engaged in protein associations and thus become functionally indispensable. For complete proteomes for which statistically significant structural data are available, scale-free network statistics based solely on the distribution of folding domains, catalogued by their number of wrapping defects, best describe the proteomic connectivity. Thus, the intermolecular connectivity may be effectively used as a measure of species complexity. Our results might contribute to explaining how interactome complexity may be achieved without a dramatic increase in genome size.

Animals↗
PubMed2003

Investigations into sequence and conformational dependence of backbone entropy, inter-basin dynamics and the Flory isolated-pair hypothesis for peptides.

The populations and transitions between Ramachandran basins are studied for combinations of the standard 20 amino acids in monomers, dimers and trimers using an implicit solvent Langevin dynamics algorithm and employing seven commonly used force-fields. Both the basin populations and inter-conversion rates are influenced by the nearest neighbor's conformation and identity, contrary to the Flory isolated-pair hypothesis. This conclusion is robust to the choice of force-field, even though the use of different force-fields produces large variations in the populations and inter-conversion rates between the dominant helical, extended beta, and polyproline II basins. The computed variation of conformational and dynamical properties with different force-fields exceeds the difference between explicit and implicit solvent calculations using the same force-field. For all force-fields, the inter-basin transitions exhibit a directional dependence, with most transitions going through extended beta conformation, even when it is the least populated basin. The implications of these results are discussed in the context of estimates for the backbone entropy of single residues, and for the ability of all-atom simulations to reproduce experimental protein folding data.

Algorithms↗
PubMed2003

Structural defects and the diagnosis of amyloidogenic propensity.

Disease-related amyloidogenic propensity has been unexpectedly found in proteins driven to adopt a monomeric uncomplexed state at high concentrations under near-physiological conditions. This situation occasionally arises in new health treatments, such as kidney dialysis. Assuming that under such conditions a partial retention of native structure takes place, this work identifies a structural characteristic indicating amyloidogenic propensity: a high density of backbone hydrogen bonds exposed to water attack in monomeric structure. On this basis, we propose a diagnostic tool based on the identification of hydrogen bonds with a paucity of intramolecular dehydration or "wrapping." We use this predictor to identify potentially pathogenic mutations that foster amyloidogenic propensity in human prions. Such mutations either enhance the intramolecular dehydration of beta-sheet hydrogen bonds, thus stabilizing the nucleus for rearrangement into the scrapie fold, or contribute to the destabilization of the cellular form by introducing additional underwrapped hydrogen bonds. Our predictions are consistent with known disease-related mutations and lead to a cogent explanation of the pathogenic nature of specific mutations affecting the cellular prion protein structural wrapping. On the other hand, a different wrapping of a very similar fold, mouse doppel, induces a dramatically different level of amyloidogenic propensity, suggesting that the packing within the fold, and not the fold itself, contains the signal for aggregation.

Amyloid↗
PubMed2003

Proteins with H-bond packing defects are highly interactive with lipid bilayers: Implications for amyloidogenesis.

We noticed that disease-related amyloidogenic proteins and especially cellular prion proteins have the highest proportion of incompletely desolvated backbone H bonds among soluble proteins. Such bonds are vulnerable to water attack and thus represent structural weaknesses. We have measured the adsorption of proteins onto phospholipid bilayers and found a strong correlation between the extent of underwrapping of backbone H bonds in the native structure of a protein and its extent of deposition on the bilayer: the less the H bond wrapping, the higher the propensity for protein-bilayer binding. These observations support the proposition that soluble proteins with amyloidogenic propensity and membrane proteins share a pervasive building motif: the underwrapped H bonds. Whereas in membrane proteins, this motif does not signal a structural vulnerability, in soluble proteins, it is responsible for their reactivity.

Adsorption↗