Dataset Information

Quantitatively characterizing the ligand binding mechanisms of choline binding protein using Markov state model analysis.

ABSTRACT: Protein-ligand recognition plays key roles in many biological processes. One of the most fascinating questions about protein-ligand recognition is to understand its underlying mechanism, which often results from a combination of induced fit and conformational selection. In this study, we have developed a three-pronged approach of Markov State Models, Molecular Dynamics simulations, and flux analysis to determine the contribution of each model. Using this approach, we have quantified the recognition mechanism of the choline binding protein (ChoX) to be ?90% conformational selection dominant under experimental conditions. This is achieved by recovering all the necessary parameters for the flux analysis in combination with available experimental data. Our results also suggest that ChoX has several metastable conformational states, of which an apo-closed state is dominant, consistent with previous experimental findings. Our methodology holds great potential to be widely applied to understand recognition mechanisms underlining many fundamental biological processes.

SUBMITTER: Gu S

PROVIDER: S-EPMC4125059 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Quantitatively characterizing the ligand binding mechanisms of choline binding protein using Markov state model analysis.

Gu Shuo S Silva Daniel-Adriano DA Meng Luming L Yue Alexander A Huang Xuhui X

PLoS computational biology 20140807 8

Protein-ligand recognition plays key roles in many biological processes. One of the most fascinating questions about protein-ligand recognition is to understand its underlying mechanism, which often results from a combination of induced fit and conformational selection. In this study, we have developed a three-pronged approach of Markov State Models, Molecular Dynamics simulations, and flux analysis to determine the contribution of each model. Using this approach, we have quantified the recognit ...[more]

PMID: 25101697

Similar Datasets

Project description:Obtaining accurate binding free energies from in silico screens has been a long-standing goal for the computational chemistry community. However, accuracy and computational cost are at odds with one another, limiting the utility of methods that perform this type of calculation. Many methods achieve massive scale by explicitly or implicitly assuming that the target protein adopts a single structure, or undergoes limited fluctuations around that structure, to minimize computational cost. Others simulate each protein-ligand complex of interest, accepting lower throughput in exchange for better predictions of binding affinities. Here, we present the PopShift framework for accounting for the ensemble of structures a protein adopts and their relative probabilities. Protein degrees of freedom are enumerated once, and then arbitrarily many molecules can be screened against this ensemble. Specifically, we use Markov state models (MSMs) as a compressed representation of a protein's thermodynamic ensemble. We start with a ligand-free MSM and then calculate how addition of a ligand shifts the populations of each protein conformational state based on the strength of the interaction between that protein conformation and the ligand. In this work we use docking to estimate the affinity between a given protein structure and ligand, but any estimator of binding affinities could be used in the PopShift framework. We test PopShift on the classic benchmark pocket T4 Lysozyme L99A. We find that PopShift is more accurate than common strategies, such as docking to a single structure and traditional ensemble docking─producing results that compare favorably with alchemical binding free energy calculations in terms of RMSE but not correlation─and may have a more favorable computational cost profile in some applications. In addition to predicting binding free energies and ligand poses, PopShift also provides insight into how the probability of different protein structures is shifted upon addition of various concentrations of ligand, providing a platform for predicting affinities and allosteric effects of ligand binding. Therefore, we expect PopShift will be valuable for hit finding and for providing insight into phenomena like allostery.

Project description:BackgroundReflexive pitch perturbation experiments are commonly used to investigate the neural mechanisms underlying vocal motor control. In these experiments, the fundamental frequency-the acoustic correlate of pitch-of a speech signal is shifted unexpectedly and played back to the speaker via headphones in near real-time. In response to the shift, speakers increase or decrease their fundamental frequency in the direction opposing the shift so that their perceived pitch is closer to what they intended. The goal of the current work is to develop a quantitative model of responses to reflexive perturbations that can be interpreted in terms of the physiological mechanisms underlying the response and that captures both group-mean data and individual subject responses.MethodsA model framework was established that allowed the specification of several models based on Proportional-Integral-Derivative and State-Space/Directions Into Velocities of Articulators (DIVA) model classes. The performance of 19 models was compared in fitting experimental data from two published studies. The models were evaluated in terms of their ability to capture both population-level responses and individual differences in sensorimotor control processes.ResultsA three-parameter DIVA model performed best when fitting group-mean data from both studies; this model is equivalent to a single-rate state-space model and a first-order low pass filter model. The same model also provided stable estimates of parameters across samples from individual subject data and performed among the best models to differentiate between subjects. The three parameters correspond to gains in the auditory feedback controller's response to a perceived error, the delay of this response, and the gain of the somatosensory feedback controller's "resistance" to this correction. Excellent fits were also obtained from a four-parameter model with an additional auditory velocity error term; this model was better able to capture multi-component reflexive responses seen in some individual subjects.ConclusionOur results demonstrate the stereotyped nature of an individual's responses to pitch perturbations. Further, we identified a model that captures population responses to pitch perturbations and characterizes individual differences in a stable manner with parameters that relate to underlying motor control capabilities. Future work will evaluate the model in characterizing responses from individuals with communication disorders.

Dataset Information

Quantitatively characterizing the ligand binding mechanisms of choline binding protein using Markov state model analysis.

Publications

Quantitatively characterizing the ligand binding mechanisms of choline binding protein using Markov state model analysis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets