Vienna-PTM web server: a toolkit for MD simulations of protein post-translational modifications

Christian Margreitter,Bojan Zagrovic,Drazen Petrov

doi:10.1093/nar/gkt416

Abstract

Post-translational modifications (PTMs) play a key role in numerous cellular processes by directly affecting structure, dynamics and interaction networks of target proteins. Despite their importance, our understanding of protein PTMs at the atomistic level is still largely incomplete. Molecular dynamics (MD) simulations, which provide high-resolution insight into biomolecular function and underlying mechanisms, are in principle ideally suited to tackle this problem. However, because of the challenges associated with the development of novel MD parameters and a general lack of suitable computational tools for incorporating PTMs in target protein structures, MD simulations of post-translationally modified proteins have historically lagged significantly behind the studies of unmodified proteins. Here, we present Vienna-PTM web server (http://vienna-ptm.univie.ac.at), a platform for automated introduction of PTMs of choice to protein 3D structures (PDB files) in a user-friendly visual environment. With 256 different enzymatic and non-enzymatic PTMs available, the server performs geometrically realistic introduction of modifications at sites of interests, as well as subsequent energy minimization. Finally, the server makes available force field parameters and input files needed to run MD simulations of modified proteins within the framework of the widely used GROMOS 54A7 and 45A3 force fields and GROMACS simulation package.

Highlights

Post-translational modifications (PTMs) of proteins, such as phosphorylation, acetylation, methylation, carboxylation or hydroxylation, play a key role in a variety of different cellular processes [1,2]
Because of the challenges associated with the development of novel Molecular dynamics (MD) parameters and a general lack of suitable computational tools for incorporating PTMs in target protein structures, MD simulations of post-translationally modified proteins have historically lagged significantly behind the studies of unmodified proteins
Amino acids often undergo a significant change in their physico-chemical properties on modification, resulting sometimes in a dramatic alteration of the structure of the affected protein, its dynamics and the way it interacts with the environment [1,10,11,12,13]

Summary

INTRODUCTION

Post-translational modifications (PTMs) of proteins, such as phosphorylation, acetylation, methylation, carboxylation or hydroxylation, play a key role in a variety of different cellular processes [1,2]. The paramount importance of such modifications is underscored by the fact that 5% of the human genome encodes enzymes related to PTMs [1] Despite their extreme biological relevance, our atomistic-level understanding of PTMs and their effect on protein structure, dynamics and interaction networks is still rudimentary. The power of MD simulations in particular and computational modeling approaches in general is expected to only increase in the future because of growing computational capabilities and ever-improving models Despite this inherent potential, simulation studies of PTMs have typically lagged behind both wet-laboratory research and simulation studies of unmodified proteins, focusing even in best cases only on. In addition to modified PDB files, the output of the server includes all relevant structure and topology files needed to run MD simulations of modified proteins using GROMACS biomolecular simulation package and one of the aforementioned two force fields

MATERIALS AND METHODS

Findings

CONCLUSIONS