[show abstract][hide abstract] ABSTRACT: Bacterial photosynthetic membranes, also known as chromatophores, are tightly packed with integral membrane proteins that work together to carry out photosynthesis. Chromatophores display a wide range of cellular morphologies; spherical, tubular, and lamellar chromatophores have all been observed in different bacterial species, or with different protein constituents. Through recent computational modeling and simulation, it has been demonstrated that the light-harvesting complexes abundant in chromatophores induce local membrane curvature via multiple mechanisms. These protein complexes assemble to generate a global curvature and sculpt the chromatophores into various cellular-scale architectures.
[show abstract][hide abstract] ABSTRACT: Recent advances in computing technology have enabled microsecond long all-atom molecular dynamics (MD) simulations of biological systems. Methods that can distill the salient features of such large trajectories are now urgently needed. Conventional clustering methods used to analyze MD trajectories suffer from various setbacks, namely (i) they are not data driven, (ii) they are unstable to noise and changes in cut-off parameters such as cluster radius and cluster number, and (iii) they do not reduce the dimensionality of the trajectories, and hence are unsuitable for finding collective coordinates. We advocate the application of principal component analysis (PCA) and a non-metric multidimensional scaling (nMDS) method to reduce MD trajectories and overcome the drawbacks of clustering. To illustrate the superiority of nMDS over other methods in reducing data and reproducing salient features, we analyze three complete villin headpiece folding trajectories. Our analysis suggests that the folding process of the villin headpiece is structurally heterogeneous.
PLoS ONE 01/2010; 5(4):e9890. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Continuing advances in development of multi-core CPUs, GPUs, and low-cost six-degree-of-freedom virtual reality input devices have created an unprecedented opportunity for broader use of interactive molecular modeling and immersive visualization of large molecular complexes. We describe the design and implementation of VMD, a popular molecular visualization and modeling tool that supports both desktop and immersive virtual reality environments, and includes support for a variety of multi-modal user interaction mechanisms. A number of unique challenges arise in supporting immersive visualization and advanced input devices within software that is used by a broad community of scientists that often have little background in the use or administration of these technologies. We share our experiences in supporting VMD on existing and upcoming low-cost virtual reality hardware platforms, and we give our perspective on how these technologies can be improved and employed to enable next-generation interactive molecular simulation tools for broader use by the molecular modeling community.
Lecture Notes in Computer Science 01/2010; 6454:382-393.
[show abstract][hide abstract] ABSTRACT: Oseltamivir (Tamiflu) is currently the frontline antiviral drug employed to fight the flu virus in infected individuals by inhibiting neuraminidase, a flu protein responsible for the release of newly synthesized virions. However, oseltamivir resistance has become a critical problem due to rapid mutation of the flu virus. Unfortunately, how mutations actually confer drug resistance is not well understood. In this study, we employ molecular dynamics (MD) and steered molecular dynamics (SMD) simulations, as well as graphics processing unit (GPU)-accelerated electrostatic mapping, to uncover the mechanism behind point mutation induced oseltamivir-resistance in both H5N1 "avian" and H1N1pdm "swine" flu N1-subtype neuraminidases. The simulations reveal an electrostatic binding funnel that plays a key role in directing oseltamivir into and out of its binding site on N1 neuraminidase. The binding pathway for oseltamivir suggests how mutations disrupt drug binding and how new drugs may circumvent the resistance mechanisms.
[show abstract][hide abstract] ABSTRACT: Experimental studies of protein folding are hampered by the fact that only low-resolution structural data can be obtained with sufficient temporal resolution. Molecular dynamics simulations offer a complementary approach, providing extremely high-resolution spatial and temporal data on folding processes. However, at present, such simulations are limited in several respects, including the inability of molecular dynamics force fields to completely reproduce the true potential energy surfaces of proteins, the need for simulations to extend to the millisecond timescale for the folding of many proteins and the difficulty inherent in obtaining sufficient sampling to properly characterize the extremely heterogeneous folding processes and then analysing those data efficiently. We review recent progress in the simulation of three common model systems for protein folding, and discuss how advances in technology and theory are allowing protein-folding simulations to address their present shortcomings.
[show abstract][hide abstract] ABSTRACT: The dynamics of excitation energy transfer within the B850 ring of light harvesting complex 2 from Rhodobacter sphaeroides and between neighboring B850 rings is investigated by means of dissipative quantum mechanics. The assumption of Boltzmann populated donor states for the calculation of intercomplex excitation transfer rates by generalized Forster theory is shown to give accurate results since intracomplex exciton relaxation to near-Boltzmann population exciton states occurs within a few picoseconds. The primary channels of exciton transfer between B850 rings are found to be the five lowest-lying exciton states, with non-850 nm exciton states making significant contributions to the total transfer rate.
The Journal of chemical physics 12/2009; 131(22):225101. · 3.09 Impact Factor
[show abstract][hide abstract] ABSTRACT: The photosynthetic apparatus of purple bacteria is contained within organelles called chromatophores, which form as extensions of the cytoplasmic membrane. The shape of these chromatophores can be spherical (as in Rhodobacter sphaeroides), lamellar (as in Rhodopseudomonas acidophila and Phaeospirillum molischianum), or tubular (as in certain Rb. sphaeroides mutants). Chromatophore shape is thought to be influenced by the integral membrane proteins Light Harvesting Complexes I and II (LH1 and LH2), which pack tightly together in the chromatophore. It has been suggested that the shape of LH2, together with its close packing in the membrane, induces membrane curvature. The mechanism of LH2-induced curvature is explored via molecular dynamics simulations of multiple LH2 complexes in a membrane patch. LH2s from three species-Rb. sphaeroides, Rps. acidophila, and Phsp. molischianum-were simulated in different packing arrangements. In each case, the LH2s pack together and tilt with respect to neighboring LH2s in a way that produces an overall curvature. This curvature appears to be driven by a combination of LH2's shape and electrostatic forces that are modulated by the presence of well-conserved cytoplasmic charged residues, the removal of which inhibits LH2 curvature. The interaction of LH2s and an LH1 monomer is also explored, and it suggests that curvature is diminished by the presence of LH1 monomers. The implications of our results for chromatophore shape are discussed.
[show abstract][hide abstract] ABSTRACT: The core complex in photosynthetic bacteria plays a central role in photosynthesis. This molecular assembly is composed of two protein complexes, viz., the light-harvesting complex I (LH1), which absorbs sunlight by means of the protein-bound bacteriochlorophylls, and the reaction center (RC), which uses the light-excitation energy absorbed by the LH complexes to produce a transmembrane (TM) charge gradient, subsequently employed for energy conversion. In Rhodobacter (Rba.) sphaeroides, the core complex contains, in addition, two copies of the single TM alpha-helix protein, PufX, and forms a (RC-LH1-PufX)(2) dimer. To this date, no high-resolution structure has been reported for the entire core complex. In particular, the location of PufX within the (RC-LH1-PufX)(2) dimer is still the subject of much debate. Here, one of the proposed locations for PufX, requiring its dimerization, is examined. The PufX-dimer model on the basis of the glycophorin A (GpA) dimer was constructed, and its robustness was probed through a series of molecular dynamics (MD) simulations. The free-energy change due to the replacement of Gly35 by valine was also determined to assess whether this mutation is responsible for distinct PufX oligomerization states in different Rba. species. The present study shows that PufX helices form a stable GpA-like dimer with a helix-helix crossing angle that could constitute the molecular basis of the reported highly bent and V-shaped structure of the Rba. sphaeroides core complex dimer.
Journal of the American Chemical Society 11/2009; 131(47):17096-8. · 10.68 Impact Factor
[show abstract][hide abstract] ABSTRACT: During protein synthesis, it is often necessary for the ribosome to form a complex with a membrane-bound channel, the SecY/Sec61 complex, in order to translocate nascent proteins across a cellular membrane. Structural data on the ribosome-channel complex are currently limited to low-resolution cryo-electron microscopy maps, including one showing a bacterial ribosome bound to a monomeric SecY complex. Using that map along with available atomic-level models of the ribosome and SecY, we have determined, through molecular dynamics flexible fitting (MDFF), an atomic-resolution model of the ribosome-channel complex. We characterized computationally the sites of ribosome-SecY interaction within the complex and determined the effect of ribosome binding on the SecY channel. We also constructed a model of a ribosome in complex with a SecY dimer by adding a second copy of SecY to the MDFF-derived model. The study involved 2.7-million-atom simulations over altogether nearly 50 ns.
[show abstract][hide abstract] ABSTRACT: BAR domains are highly conserved protein domains participating in a diversity of cellular processes that involve membrane remodeling. The mechanisms underlying such remodeling are debated. For the relatively well-studied case of amphiphysin N-BAR domain, one suggested mechanism involves scaffolding, i.e., binding of a negatively charged membrane to the protein's positively charged curved surface. An alternative mechanism suggests that insertion of the protein's N-terminal amphipathic segments (N-helices H0) into the membrane leads to bending. Here, we address the issue through all-atom and coarse-grained simulations of multiple amphiphysin N-BAR domains and their components interacting with a membrane. We observe that complete N-BAR domains and BAR domains without H0s bend the membrane, but H0s alone do not, which suggests that scaffolding, rather than helix insertion, plays a key role in membrane sculpting by amphiphysin N-BAR domains.
[show abstract][hide abstract] ABSTRACT: Expression of the Escherichia coli tryptophanase operon depends on ribosome stalling during translation of the upstream TnaC leader peptide, a process for which interactions between the TnaC nascent chain and the ribosomal exit tunnel are critical. We determined a 5.8 angstrom-resolution cryo-electron microscopy and single-particle reconstruction of a ribosome stalled during translation of the tnaC leader gene. The nascent chain was extended within the exit tunnel, making contacts with ribosomal components at distinct sites. Upon stalling, two conserved residues within the peptidyltransferase center adopted conformations that preclude binding of release factors. We propose a model whereby interactions within the tunnel are relayed to the peptidyltransferase center to inhibit translation. Moreover, we show that nascent chains adopt distinct conformations within the ribosomal exit tunnel.
[show abstract][hide abstract] ABSTRACT: Molecular dynamics simulations of protein folding can provide very high-resolution data on the folding process; however, due to computational challenges most studies of protein folding have been limited to small peptides, or made use of approximations such as Gō potentials or implicit solvent models. We have performed a set of molecular dynamics simulations totaling >50 micros on the villin headpiece subdomain, one of the most stable and fastest-folding naturally occurring proteins, in explicit solvent. We find that the wild-type villin headpiece reliably folds to a native conformation on timescales similar to experimentally observed folding, but that a fast folding double-norleucine mutant shows significantly more heterogeneous behavior. Along with other recent simulation studies, we note the occurrence of nonnative structures intermediates, which may yield a nativelike signal in the fluorescence measurements typically used to study villin folding. Based on the wild-type simulations, we propose alternative approaches to measure the formation of the native state.