Biology subjects

Beyerle, E. R.

Publications and source records attributed to Beyerle, E. R..

2 recordsLinked to original sources

bioRxiv2021

Comparison between slow, anisotropic LE4PD fluctuations and thePrincipal Component Analysis modes of Ubiquitin

Proteins biological function and folding mechanisms are often guided by large-scale, slow motions, which involve crossing high energy barriers. In a simulation trajectory, these slow fluctuations are commonly identified using a principal component analysis (PCA). Despite the popularity of this method, a complete analysis of its predictions based on the physics of protein motion has been so far limited. This study formally connects the PCA to a Langevin model of protein dynamics and analyzes the contributions of energy barriers and hydrodynamic interactions to the slow PCA modes of motion. To do so, we introduce an anisotropic extension of the Langevin Equation for Protein Dynamics, called the LE4PD-XYZ, which formally connects to the PCA essential dynamics. The LE4PD-XYZ is an accurate coarse-grained diffusive method to model protein motion, which describes anisotropic fluctuations in the proteins alpha-carbons. The LE4PD accounts for hydrodynamic effects and mode-dependent free-energy barriers. This study compares large-scale anisotropic fluctuations identified by the LE4PD-XYZ to the mode-dependent PCAs predictions, starting from a microsecond-long alpha-carbon molecular dynamics atomistic trajectory of the protein ubiquitin. We observe that the inclusion of free-energy barriers and hydrodynamic interactions has important effects on the identification and timescales of ubiquitins slow modes.

biophysics↗

bioRxiv2020

Dinucleotides as simple models of the base stacking-unstacking component of DNA 'breathing' mechanisms

Regulatory protein access to the DNA duplex interior depends on local DNA breathing fluctuations, and the most fundamental of these are thermally-driven base stacking-unstacking interactions. The smallest DNA unit that can undergo such transitions is the dinucleotide, whose structural and dynamic properties are dominated by stacking, while the ion condensation, cooperative stacking and inter-base hydrogen-bonding, present in duplex DNA are not involved. We use dApdA to study stacking-unstacking at the dinucleotide level because the fluctuations observed are likely to resemble those of larger DNA molecules, but in the absence of constraints introduced by cooperativity are likely to be more pronounced, and thus more accessible to measurement. We study these fluctuations with a combination of Molecular Dynamics simulations on the microsecond timescale and Markov State Model analyses, and validate our results by calculations of circular dichroism (CD) spectra, with results that agree well with experiments. Our analyses show that the CD spectrum of dApdA is defined by two distinct chiral conformations that correspond, respectively, to a Watson-Crick form and a hybrid form with one base in a Hoogsteen configuration. We find also that ionic structure and water orientation around dApdA play important roles in controlling its breathing fluctuations.

biophysics↗