Biomedical subjects

K Y Sanbonmatsu

Publications and source records attributed to K Y Sanbonmatsu.

7 recordsLinked to original sources

PubMed2006

High performance computing in biology: multimillion atom simulations of nanoscale systems.

Computational methods have been used in biology for sequence analysis (bioinformatics), all-atom simulation (molecular dynamics and quantum calculations), and more recently for modeling biological networks (systems biology). Of these three techniques, all-atom simulation is currently the most computationally demanding, in terms of compute load, communication speed, and memory load. Breakthroughs in electrostatic force calculation and dynamic load balancing have enabled molecular dynamics simulations of large biomolecular complexes. Here, we report simulation results for the ribosome, using approximately 2.64 million atoms, the largest all-atom biomolecular simulation published to date. Several other nano-scale systems with different numbers of atoms were studied to measure the performance of the NAMD molecular dynamics simulation program on the Los Alamos National Laboratory Q Machine. We demonstrate that multimillion atom systems represent a 'sweet spot' for the NAMD code on large supercomputers. NAMD displays an unprecedented 85% parallel scaling efficiency for the ribosome system on 1024 CPUs. We also review recent targeted molecular dynamics simulations of the ribosome that prove useful for studying conformational changes of this large biomolecular complex in atomic detail.

Computational Biology↗

PubMed2006

Energy landscape of the ribosomal decoding center.

The ribosome decodes the genetic information that resides in nucleic acids. A key component of the decoding mechanism is a conformational switch in the decoding center of the small ribosomal subunit discovered in high-resolution X-ray crystallography studies. It is known that small subunit nucleotides A1492 and A1493 flip out of helix 44 upon transfer RNA (tRNA) binding; however, the operation principles of this switch remain unknown. Replica molecular dynamics simulations reveal a low free energy barrier between flipped-out and flipped-in states, consistent with a switch that can be controlled by shifting the equilibrium between states. The barrier determined by the simulations is sufficiently small for the binding of ligands, such as tRNAs or aminoglycoside antibiotics, to shift the equilibrium.

Algorithms↗

PubMed2006

Alignment/misalignment hypothesis for tRNA selection by the ribosome.

Transfer RNAs (tRNAs) are the adaptor molecules that allow the ribosome to decode genetic information during protein synthesis. During decoding, the ribosome must chose the tRNA whose anticodon corresponds to the codon inscribed in the messenger RNA to incorporate the correct amino acid into the growing polypeptide chain. Fidelity is improved dramatically by a GTP hydrolysis event. Information about the correctness of the anticodon must be sent from the decoding center to the elongation factor, EF-Tu, where the GTP hydrolysis takes place. A second discrimination event entails the accommodation of the aminoacyl-tRNA into its fully bound A/A state inside the ribosome. Here, we present a hypothesis for a specific mechanism of signal transduction through the tRNA, which operates during GTPase activation and accommodation. We propose that the rigidity of the tRNA plays an important role in the transmission of the decoding signal. While the tRNA must flex during binding and accommodation, its anisotropic stiffness enables precise positioning of the acceptor arm in the A/T state, the A/A state and the accommodation corridor. Correct alignment will result in optimal GTPase activation and accommodation rates. Incorrect tRNAs, however, whose anticodons are misaligned, will also have acceptor arms that are misaligned, resulting in sub-optimal GTPase activation and accommodation rates. In the case of GTPase activation, it is possible that the misalignment of the acceptor arm affects the rate directly, by altering the conformational change of the switch region of EF-Tu, or indirectly, by changing the alignment of EF-Tu with respect to the sarcin-ricin loop (SRL) of the large ribosomal subunit.

Anticodon↗

PubMed2003

Understanding discrimination by the ribosome: stability testing and groove measurement of codon-anticodon pairs.

The ribosome must discriminate between correct and incorrect tRNAs with sufficient speed and accuracy to sustain an adequate rate of cell growth. Here, we report the results of explicit solvent molecular dynamics simulations, which address the mechanism of discrimination by the ribosome. The universally conserved 16S rRNA base A1493 and the kink in mRNA between A and P sites amplify differences in stability between cognate and near-cognate codon-anticodon pairs. Destabilization by the mRNA kink also provides a geometric explanation for the higher error rates observed for mismatches in the first codon position relative to mismatches in the second codon position. For more stable near-cognates, the repositioning of the universally conserved bases A1492 and G530 results in increased solvent exposure and an uncompensated loss of hydrogen bonds, preventing correct codon-anticodon-ribosome interactions from forming.

Anticodon↗

PubMed2002

Structure of Met-enkephalin in explicit aqueous solution using replica exchange molecular dynamics.

Replica exchange molecular dynamics (MD) simulations of Met-enkephalin in explicit solvent reveal helical and nonhelical structures. Four predominant structures of Met-enkephalin are sampled with comparable probabilities (two helical and two nonhelical). The energy barriers between these configurations are low, suggesting that Met-enkephalin switches easily between configurations. This is consistent with the requirement that Met-enkephalin be sufficiently flexible to bind to several different receptors. Replica exchange simulations of 32 ns are shown to sample approximately five times more configurational space than constant temperature MD simulations of the same duration. The energy landscape for the replica exchange simulation is presented. A detailed study of replica trajectories demonstrates that the significant increases in temperature provided by the replica exchange technique enable transitions from nonhelical to helical structures that would otherwise be prevented by kinetic trapping. Met-enkephalin (Type Entrez Proteins; Value A61445; Service Entrez Proteins).

Algorithms↗

PubMed2001

Exploring the energy landscape of a beta hairpin in explicit solvent.

We studied the energy landscape of the peptide Ace-GEWTYDDATKTFTVTE-Nme, taken from the C-terminal fragment (41-56) of protein G, in explicit aqueous solution by a highly parallel replica-exchange approach that combines molecular dynamics trajectories with a temperature exchange Monte Carlo process. The combined trajectories in T and configurational space allow a replica to overcome a free energy barrier present at one temperature by increasing T, changing configurations, and cooling in a self-regulated manner, thus allowing sampling of broad regions of configurational space in short (nanoseconds) time scales. The free energy landscape of this system over a wide range of temperatures shows that the system preferentially adopts a beta hairpin structure. However, the peptide also samples other stable ensembles where the peptide adopts helices and helix-turn-helix states, among others. The helical states become increasingly stable at low temperatures, but are slightly less stable than the beta turn ensemble. The energy landscape is rugged at low T, where substates are separated by large energy barriers. These barriers disappear at higher T (approximately 330 K), where the system preferentially adopts a "molten globule" state with structures similar to the beta hairpin.

Amino Acid Sequence↗

PubMed2001

Shear viscosity of strongly coupled Yukawa systems on finite length scales.

The Yukawa shear viscosity has been calculated using nonequilibrium molecular dynamics. Near the viscosity minimum, we find exponential decay consistent with the Navier-Stokes equation, with significant deviations on finite length scales for larger viscosity values. The viscosity is determined to be nonlocal on a scale length consistent with the correlation length, revealing the length scales necessary for obtaining transport coefficients in the hydrodynamic limit by nonequilibrium molecular dynamics methods. Our results are quasiuniversal with respect to excess entropy for excess entropies well below unity.

Journal Article↗