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Samantray, S.

Publications and source records attributed to Samantray, S..

2 recordsLinked to original sources
bioRxiv2020

Thermodynamics and kinetics of the amyloid-β peptide revealed by Markov state models based on MD data in agreement with experiment

The amlyoid-{beta} peptide (A{beta}) is closely linked to the development of Alzheimers disease. Molecular dynamics (MD) simulations have become an indispensable tool for studying the behavior of this peptide at the (sub)molecular level, thereby providing insight into the molecular basis of Alzheimers disease. General key aspects of MD simulations are the force field used for modeling the peptide or protein and its environment, which is important for accurate modeling of the system of interest, and the length of the simulations, which determines whether or not equilibrium is reached. In this study we address these points by analyzing 30-{micro}s MD simulations acquired for A{beta}40 using seven different force fields. We assess the convergence of these simulations based on the convergence of various structural properties and of NMR and fluorescence spectroscopic observables. Moreover, we calculate Markov state models for each of the seven MD simulations, which provide an unprecedented view of the thermodynamics and kinetics of the amyloid-{beta} peptide. This further allows us to provide answers for pertinent questions, like: Which force fields are suitable for modeling A{beta}? (a99SB-UCB and a99SB-ILDN/TIP4P-D); What does A{beta} peptide really look like? (mostly extended and disordered) and; How long does it take MD simulations of A{beta} to attain equilibrium? (20-30 {micro}s). We believe the analyses presented in this study will provide a useful reference guide for important questions relating to the structure and dynamics of A{beta}in particular, and by extension other similar disordered peptides.

biophysics↗
bioRxiv2020

Molecular dynamics simulations of protein aggregation: protocols for simulation setup and analysis with Markov state models and transition networks

Protein disorder and aggregation play significant roles in the pathogenesis of numerous neuro-degenerative diseases, such as Alzheimers and Parkinsons disease. The end products of the aggregation process in these diseases are {beta}-sheet rich amyloid fibrils. Though in most cases small, soluble oligomers formed during amyloid aggregation are the toxic species. A full understanding of the physicochemical forces behind the protein aggregation process is required if one aims to reveal the molecular basis of the various amyloid diseases. Among a multitude of biophysical and biochemical techniques that are employed for studying protein aggregation, molecular dynamics (MD) simulations at the atomic level provide the highest temporal and spatial resolution of this process, capturing key steps during the formation of amyloid oligomers. Here we provide a step-by-step guide for setting up, running, and analyzing MD simulations of aggregating peptides using GROMACS. For the analysis we provide the scripts that were developed in our lab, which allow to determine the oligomer size and inter-peptide contacts that drive the aggregation process. Moreover, we explain and provide the tools to derive Markov state models and transition networks from MD data of peptide aggregation.

biophysics↗