Exploring the Photophysical Properties of Molecular Systems Using Excited State Accelerated ab Initio Molecular Dynamics.

In the present work, we employ excited state accelerated ab initio molecular dynamics (A-AIMD) to efficiently study the excited state energy landscape and photophysical topology of a variety of molecular systems. In particular, we focus on two important challenges for the modeling of excited electronic states: (i) the identification and characterization of conical intersections and crossing seams, in order to predict different and often competing radiationless decay mechanisms, and (ii) the description of the solvent effect on the absorption and emission spectra of chemical species in solution. In particular, using as examples the Schiff bases formaldimine and salicylidenaniline, we show that A-AIMD can be readily employed to explore the conformational space around crossing seams in molecular systems with very different photochemistry. Using acetone in water as an example, we demonstrate that the enhanced configurational space sampling may be used to accurately and efficiently describe both the prominent features and line-shapes of absorption and emission spectra

Enhanced conformational space sampling improves the prediction of chemical shifts in proteins.

A biased-potential molecular dynamics simulation method, accelerated molecular dynamics (AMD), was combined with the chemical shift prediction algorithm SHIFTX to calculate (1)H(N), (15)N, (13)Calpha, (13)Cbeta, and (13)C' chemical shifts of the ankyrin repeat protein IkappaBalpha (residues 67-206), the primary inhibitor of nuclear factor kappa-B (NF-kappaB). Free-energy-weighted molecular ensembles were generated over a range of acceleration levels, affording systematic enhancement of the conformational space sampling of the protein. We have found that the predicted chemical shifts, particularly for the (15)N, (13)Calpha, and (13)Cbeta nuclei, improve substantially with enhanced conformational space sampling up to an optimal acceleration level. Significant improvement in the predicted chemical shift data coincides with those regions of the protein that exhibit backbone dynamics on longer time scales. Interestingly, the optimal acceleration level for reproduction of the chemical shift data has previously been shown to best reproduce the experimental residual dipolar coupling (RDC) data for this system, as both chemical shift data and RDCs report on an ensemble and time average in the millisecond range

Functional dynamics of the folded ankyrin repeats of I kappa B alpha revealed by nuclear magnetic resonance.

Inhibition of nuclear factor kappaB (NF-kappaB) is mainly accomplished by IkappaB alpha, which consists of a signal response sequence at the N-terminus, a six-ankyrin repeat domain (ARD) that binds NF-kappaB, and a C-terminal PEST sequence. Previous studies with the ARD revealed that the fifth and sixth repeats are only partially folded in the absence of NF-kappaB. Here we report NMR studies of a truncated version of IkappaB alpha, containing only the first four ankyrin repeats, IkappaB alpha(67-206). This four-repeat segment is well-structured in the free state, enabling full resonance assignments to be made. H-D exchange, backbone dynamics, and residual dipolar coupling (RDC) experiments reveal regions of flexibility. In addition, regions consistent with the presence of micro- to millisecond motions occur periodically throughout the repeat structure. Comparison of the RDCs with the crystal structure gave only moderate agreement, but an ensemble of structures generated by accelerated molecular dynamics gave much better agreement with the measured RDCs. The regions showing flexibility correspond to those implicated in entropic compensation for the loss of flexibility in ankyrin repeats 5 and 6 upon binding to NF-kappaB. The regions showing micro- to millisecond motions in the free protein are the ends of the beta-hairpins that directly interact with NF-kappaB in the complex

Mechanism of glycan receptor recognition and specificity switch for avian, swine, and human adapted influenza virus hemagglutinins: a molecular dynamics perspective.

Hemagglutinins (HA's) from duck, swine, and human influenza viruses have previously been shown to prefer avian and human glycan receptor analogues with distinct topological profiles, pentasaccharides LSTa (alpha-2,3 linkage) and LSTc (alpha-2,6 linkage), in comparative molecular dynamics studies. On the basis of detailed analyses of the dynamic motions of the receptor binding domains (RBDs) and interaction energy profiles with individual glycan residues, we have identified approximately 30 residue positions in the RBD that present distinct profiles with the receptor analogues. Glycan binding constrained the conformational space sampling by the HA. Electrostatic steering appeared to play a key role in glycan binding specificity. The complex dynamic behaviors of the major SSE and trimeric interfaces with or without bound glycans suggested that networks of interactions might account for species specificity in these low affinity and high avidity (multivalent) interactions between different HA and glycans. Contact frequency, energetic decomposition, and H-bond analyses revealed species-specific differences in HA-glycan interaction profiles, not readily discernible from crystal structures alone. Interaction energy profiles indicated that mutation events at the set of residues such as 145, 156, 158, and 222 would favor human or avian receptor analogues, often through interactions with distal asialo-residues. These results correlate well with existing experimental evidence, and suggest new opportunities for simulation-based vaccine and drug development

Adaptive Accelerated Molecular Dynamics (Ad-AMD) Revealing the Molecular Plasticity of P450cam

An extended accelerated molecular dynamics (AMD) methodology called adaptive AMD is presented. Adaptive AMD (Ad-AMD) is an efficient and robust conformational space sampling algorithm that is particularly-well suited to proteins with highly structured potential energy surfaces exhibiting complex, large-scale collective conformational transitions. Ad-AMD simulations of substrate-free P450cam reveal that this system exists in equilibrium between a fully and partially open conformational state. The mechanism for substrate binding depends on the size of the ligand. Larger ligands enter the P450cam binding pocket, and the resulting substrate-bound system is trapped in an open conformation via a population shift mechanism. Small ligands, which fully enter the binding pocket, cause an induced-fit mechanism, resulting in the formation of an energetically stable closed conformational state. These results are corroborated by recent experimental studies and potentially provide detailed insight into the functional dynamics and conformational behavior of the entire cytochrome-P450 superfamily

The Dynamic Structure of Thrombin in Solution

AbstractThe backbone dynamics of human α-thrombin inhibited at the active site serine were analyzed using R1, R2, and heteronuclear NOE experiments, variable temperature TROSY 2D [1H-15N] correlation spectra, and Rex measurements. The N-terminus of the heavy chain, which is formed upon zymogen activation and inserts into the protein core, is highly ordered, as is much of the double beta-barrel core. Some of the surface loops, by contrast, remain very dynamic with order parameters as low as 0.5 indicating significant motions on the ps-ns timescale. Regions of the protein that were thought to be dynamic in the zymogen and to become rigid upon activation, in particular the γ-loop, the 180s loop, and the Na+ binding site have order parameters below 0.8. Significant Rex was observed in most of the γ-loop, in regions proximal to the light chain, and in the β-sheet core. Accelerated molecular dynamics simulations yielded a molecular ensemble consistent with measured residual dipolar couplings that revealed dynamic motions up to milliseconds. Several regions, including the light chain and two proximal loops, did not appear highly dynamic on the ps-ns timescale, but had significant motions on slower timescales

Observations of chemical differentiation in clumpy molecular clouds

We have extensively mapped a sample of dense molecular clouds (L1512, TMC-1C, L1262, Per 7, L1389, L1251E) in lines of HC3N, CH3OH, SO and C^{18}O. We demonstrate that a high degree of chemical differentiation is present in all of the observed clouds. We analyse the molecular maps for each cloud, demonstrating a systematic chemical differentiation across the sample, which we relate to the evolutionary state of the cloud. We relate our observations to the cloud physical, kinematical and evolutionary properties, and also compare them to the predictions of simple chemical models. The implications of this work for understanding the origin of the clumpy structures and chemical differentiation observed in dense clouds are discussed.Comment: 20 pages, 7 figures. Higher quality figures appear in the published journal articl

On the Use of Accelerated Molecular Dynamics to Enhance Configurational Sampling in Ab Initio Simulations

We have implemented the accelerated molecular dynamics approach (Hamelberg, D.; Mongan, J.; McCammon, J. A. J. Chem. Phys. 2004, 120 (24), 11919) in the framework of ab initio MD (AIMD). Using three simple examples, we demonstrate that accelerated AIMD (A-AIMD) can be used to accelerate solvent relaxation in AIMD simulations and facilitate the detection of reaction coordinates: (i) We show, for one cyclohexane molecule in the gas phase, that the method can be used to accelerate the rate of the chair-to-chair interconversion by a factor of ∼1 × 105, while allowing for the reconstruction of the correct canonical distribution of low-energy states; (ii) We then show, for a water box of 64 H2O molecules, that A-AIMD can also be used in the condensed phase to accelerate the sampling of water conformations, without affecting the structural properties of the solvent; and (iii) The method is then used to compute the potential of mean force (PMF) for the dissociation of Na−Cl in water, accelerating the convergence by a factor of ∼3−4 compared to conventional AIMD simulations.(2) These results suggest that A-AIMD is a useful addition to existing methods for enhanced conformational and phase-space sampling in solution. While the method does not make the use of collective variables superfluous, it also does not require the user to define a set of collective variables that can capture all the low-energy minima on the potential energy surface. This property may prove very useful when dealing with highly complex multidimensional systems that require a quantum mechanical treatment

Period and chemical evolution of SC stars

The SC and CS stars are thermal-pulsing AGB stars with C/O ratio close to unity. Within this small group, the Mira variable BH Cru recently evolved from spectral type SC (showing ZrO bands) to CS (showing weak C2). Wavelet analysis shows that the spectral evolution was accompanied by a dramatic period increase, from 420 to 540 days, indicating an expanding radius. The pulsation amplitude also increased. Old photographic plates are used to establish that the period before 1940 was around 490 days. Chemical models indicate that the spectral changes were caused by a decrease in stellar temperature, related to the increasing radius. There is no evidence for a change in C/O ratio. The evolution in BH Cru is unlikely to be related to an on-going thermal pulse. Periods of the other SC and CS stars, including nine new periods, are determined. A second SC star, LX Cyg, also shows evidence for a large increase in period, and one further star shows a period inconsistent with a previous determination. Mira periods may be intrinsically unstable for C/O ~ 1; possibly because of a feedback between the molecular opacities, pulsation amplitude, and period. LRS spectra of 6 SC stars suggest a feature at wavelength > 15 micron, which resembles one recently attributed to the iron-sulfide troilite. Chemical models predict a large abundance of FeS in SC stars, in agreement with the proposed association.Comment: 14 pages, 20 figures. MNRAS, 2004, accepted for publication. Janet Mattei, one of the authors, died on 22 March, 2004. This paper is dedicated to her memor