Biomedical subjects

Kevin Y Sanbonmatsu

Publications and source records attributed to Kevin Y Sanbonmatsu.

5 recordsLinked to original sources

PubMed2005

Simulating movement of tRNA into the ribosome during decoding.

Decoding is the key step during protein synthesis that enables information transfer from RNA to protein, a process critical for the survival of all organisms. We have used large-scale (2.64 x 10(6) atoms) all-atom simulations of the entire ribosome to understand a critical step of decoding. Although the decoding problem has been studied for more than four decades, the rate-limiting step of cognate tRNA selection has only recently been identified. This step, known as accommodation, involves the movement inside the ribosome of the aminoacyl-tRNA from the partially bound "A/T" state to the fully bound "A/A" state. Here, we show that a corridor of 20 universally conserved ribosomal RNA bases interacts with the tRNA during the accommodation movement. Surprisingly, the tRNA is impeded by the A-loop (23S helix 92), instead of enjoying a smooth transition to the A/A state. In particular, universally conserved 23S ribosomal RNA bases U2492, C2556, and C2573 act as a 3D gate, causing the acceptor stem to pause before allowing entrance into the peptidyl transferase center. Our simulations demonstrate that the flexibility of the acceptor stem of the tRNA, in addition to flexibility of the anticodon arm, is essential for tRNA selection. This study serves as a template for simulating conformational changes in large (>10(6) atoms) biological and artificial molecular machines.

Biological Transport↗

PubMed2004

Atomic model of the Thermus thermophilus 70S ribosome developed in silico.

The ribosome is a large molecular complex that consists of at least three ribonucleic acid molecules and a large number of proteins. It translates genetic information from messenger ribonucleic acid and makes protein accordingly. To better understand ribosomal function and provide information for designing biochemical experiments require knowledge of the complete structure of the ribosome. For expanding the structural information of the ribosome, we took on the challenge of developing a detailed Thermus thermophilus ribosomal structure computationally. By combining information derived from the low-resolution x-ray structure of the 70S ribosome (providing the overall fold), high-resolution structures of the ribosomal subunits (providing the local structure), sequences, and secondary structures, we have developed an atomic model of the T. thermophilus ribosome using a homology modeling approach. Our model is stereochemically sound with a consistent single-species sequence. The overall folds of the three ribosomal ribonucleic acids in our model are consistent with those in the low-resolution crystal structure (root mean-square differences are all <1.9 angstroms). The large overall interface area (approximately 2500 angstroms2) of intersubunit bridges B2a, B3, and B5, and the inherent flexibility in regions connecting the contact residues are consistent with these bridges serving as anchoring patches for the ratcheting and rolling motions between the two subunits during translocation.

Computer Simulation↗

PubMed2003

Peptide folding simulations.

Developments in the design of small peptides that mimic proteins in complexity, recent advances in nanosecond time-resolved spectroscopy methods to study peptides and the development of modern, highly parallel simulation algorithms have come together to give us a detailed picture of peptide folding dynamics. Two newly implemented simulation techniques, parallel replica dynamics and replica exchange molecular dynamics, can now describe directly from simulations the kinetics and thermodynamics of peptide formation, respectively. Given these developments, the simulation community now has the tools to verify and validate simulation protocols and models (forcefields).

Computer Simulation↗

PubMed2002

Alpha-helical stabilization by side chain shielding of backbone hydrogen bonds.

We study atomic models of the thermodynamics of the structural transition of peptides that form alpha-helices. The effect of sequence variation on alpha-helix formation for alanine-rich peptides, Ac-Ala21-methyl amide (A21) and Ac-A5 (AAARA)3A-methyl amide (Fs peptide), is investigated by atomic simulation studies of the thermodynamics of the helix-coil transition in explicit water. The simulations show that the guanidinium group in the Arg side chains in the Fs peptide interacts with the carbonyl group four amino acids upstream in the chain and desolvates backbone hydrogen bonds. This desolvation can be directly correlated with a higher probability of hydrogen bond formation. We find that Fs has higher helical content than A21 at all temperatures. A small modification in the amber force field reproduces the experimental helical content and helix-coil transition temperatures for the Fs peptide.

Algorithms↗

PubMed2002

All-atom homology model of the Escherichia coli 30S ribosomal subunit.

Understanding the structural basis of ribosomal function requires close comparison between biochemical and structural data. Although a large amount of biochemical data are available for the Escherichia coli ribosome, the structure has not been solved to atomic resolution. Using a new RNA homology procedure, we have modeled the all-atom structure of the E. coli 30S ribosomal subunit. We find that the tertiary structure of the ribosome core, including the A-, P- and E-sites, is highly conserved. The hypervariable regions in our structure, which differ from the structure of the 30S ribosomal subunit from Thermus thermophilus, are consistent with the cryo-EM map of the E. coli ribosome.

Base Sequence↗