Biomedical subjects

Sanghyun Park

Publications and source records attributed to Sanghyun Park.

8 recordsLinked to original sources

PubMed2006

Parallelized-over-parts computation of absolute binding free energy with docking and molecular dynamics.

We present a technique for biomolecular free energy calculations that exploits highly parallelized sampling to significantly reduce the time to results. The technique combines free energies for multiple, nonoverlapping configurational macrostates and is naturally suited to distributed computing. We describe a methodology that uses this technique with docking, molecular dynamics, and free energy perturbation to compute absolute free energies of binding quickly compared to previous methods. The method does not require a priori knowledge of the binding pose as long as the docking technique used can generate reasonable binding modes. We demonstrate the method on the protein FKBP12 and eight of its inhibitors.

Biophysics↗

PubMed2006

Validation of Markov state models using Shannon's entropy.

Markov state models are kinetic models built from the dynamics of molecular simulation trajectories by grouping similar configurations into states and examining the transition probabilities between states. Here we present a procedure for validating the underlying Markov assumption in Markov state models based on information theory using Shannon's entropy. This entropy method is applied to a simple system and is compared with the previous eigenvalue method. The entropy method also provides a way to identify states that are least Markovian, which can then be divided into finer states to improve the model.

Bayes Theorem↗

PubMed2005

A new set of molecular mechanics parameters for hydroxyproline and its use in molecular dynamics simulations of collagen-like peptides.

Recently, the importance of proline ring pucker conformations in collagen has been suggested in the context of hydroxylation of prolines. The previous molecular mechanics parameters for hydroxyproline, however, do not reproduce the correct pucker preference. We have developed a new set of parameters that reproduces the correct pucker preference. Our molecular dynamics simulations of proline and hydroxyproline monomers as well as collagen-like peptides, using the new parameters, support the theory that the role of hydroxylation in collagen is to stabilize the triple helix by adjusting to the right pucker conformation (and thus the right phi angle) in the Y position.

Collagen↗

PubMed2005

Foldamer dynamics expressed via Markov state models. I. Explicit solvent molecular-dynamics simulations in acetonitrile, chloroform, methanol, and water.

In this article, we analyze the folding dynamics of an all-atom model of a polyphenylacetylene (pPA) 12-mer in explicit solvent for four common organic and aqueous solvents: acetonitrile, chloroform, methanol, and water. The solvent quality has a dramatic effect on the time scales in which pPA 12-mers fold. Acetonitrile was found to manifest ideal folding conditions as suggested by optimal folding times on the order of approximately 100-200 ns, depending on temperature. In contrast, chloroform and water were observed to hinder the folding of the pPA 12-mer due to extreme solvation conditions relative to acetonitrile; chloroform denatures the oligomer, whereas water promotes aggregation and traps. The pPA 12-mer in a pure methanol solution folded in approximately 400 ns at 300 K, compared relative to the experimental 12-mer folding time of approximately 160 ns measured in a 1:1 v/v THF/methanol solution. Requisite in drawing the aforementioned conclusions, analysis techniques based on Markov state models are applied to multiple short independent trajectories to extrapolate the long-time scale dynamics of the 12-mer in each respective solvent. We review the theory of Markov chains and derive a method to impose detailed balance on a transition-probability matrix computed from simulation data.

Acetonitriles↗

PubMed2005

Foldamer dynamics expressed via Markov state models. II. State space decomposition.

The structural landscape of poly-phenylacetylene (pPA), otherwise known as m-phenylene ethynylene oligomers, has been shown to consist of a very diverse set of conformations, including helices, turns, and knots. Defining a state space decomposition to classify these conformations into easily identifiable states is an important step in understanding the dynamics in relation to Markov state models. We define the state decomposition of pPA oligomers in terms of the sequence of discretized dihedral angles between adjacent phenyl rings along the oligomer backbone. Furthermore, we derive in mathematical detail an approach to further reduce the number of states by grouping symmetrically equivalent states into a single parent state. A more challenging problem requires a formal definition for knotted states in the structural landscape. Assuming that the oligomer chain can only cross the ideal helix path once, we propose a technique to define a knotted state derived from a helical state determined by the position along the helical nucleus where the chain crosses the ideal helix path. Several examples of helical states and knotted states from the pPA 12-mer illustrate the principles outlined in this article.

Acetylene↗

PubMed2004

Excitation migration in trimeric cyanobacterial photosystem I.

A structure-based description of excitation migration in multireaction center light harvesting systems is introduced. The description is an extension of the sojourn expansion, which decomposes excitation migration in terms of repeated detrapping and recapture events. The approach is applied to light harvesting in the trimeric form of cyanobacterial photosystem I (PSI). Excitation is found to be shared between PSI monomers and the chlorophylls providing the strongest respective links are identified. Excitation sharing is investigated by computing cross-monomer excitation trapping probabilities. It is seen that on the average there is a nearly 40% chance of excitation cross transfer and trapping, indicating efficient coupling between monomers. The robustness and optimality of the chlorophyll network of trimeric PSI is examined.

Chlorophyll↗

PubMed2004

Calculating potentials of mean force from steered molecular dynamics simulations.

Steered molecular dynamics (SMD) permits efficient investigations of molecular processes by focusing on selected degrees of freedom. We explain how one can, in the framework of SMD, employ Jarzynski's equality (also known as the nonequilibrium work relation) to calculate potentials of mean force (PMF). We outline the theory that serves this purpose and connects nonequilibrium processes (such as SMD simulations) with equilibrium properties (such as the PMF). We review the derivation of Jarzynski's equality, generalize it to isobaric--isothermal processes, and discuss its implications in relation to the second law of thermodynamics and computer simulations. In the relevant regime of steering by means of stiff springs, we demonstrate that the work on the system is Gaussian-distributed regardless of the speed of the process simulated. In this case, the cumulant expansion of Jarzynski's equality can be safely terminated at second order. We illustrate the PMF calculation method for an exemplary simulation and demonstrate the Gaussian nature of the resulting work distribution.

Computer Simulation↗

PubMed2002

Energetics of glycerol conduction through aquaglyceroporin GlpF.

Aquaglyceroporin GlpF selectively conducts water and linear polyalcohols, such as glycerol, across the inner membrane of Escherichia coli. We report steered molecular dynamics simulations of glycerol conduction through GlpF, in which external forces accelerate the transchannel conduction in a manner that preserves the intrinsic conduction mechanism. The simulations reveal channel-glycerol hydrogen bonding interactions and the stereoselectivity of the channel. Employing Jarzynski's identity between free energy and irreversible work, we reconstruct the potential of mean force along the conduction pathway through a time series analysis of molecular dynamics trajectories. This potential locates binding sites and barriers inside the channel; it also reveals a low energy periplasmic vestibule suited for efficient uptake of glycerol from the environment.

Aquaporins↗