Probing the Structure and Dynamics of Proteins by Combining Molecular Dynamics Simulations and Experimental NMR Data

Abstract

NMR experiments provide detailed structural information about biological macromolecules in solution. However, the amount of information obtained is usually much less than the number of degrees of freedom of the macromolecule. Moreover, the relationships between experimental observables and structural information, such as interatomic distances or dihedral angle values, may be multiple-valued and may rely on empirical parameters and approximations. The extraction of structural information from experimental data is further complicated by the time- and ensemble-averaged nature of NMR observables. Combining NMR data with molecular dynamics simulations can elucidate and alleviate some of these problems, as well as allow inconsistencies in the NMR data to be identified. Here, we use a number of examples from our work to highlight the power of molecular dynamics simulations in providing a structural interpretation of solution NMR data.

Molecular dynamics simulations with replica-averaged structural restraints generate structural ensembles according to the maximum entropy principle

“…Since the early implementations of this approach in the case of the replica-averaged NOE distance restraints, 13,15,16 a variety of restraining algorithms, including simultaneous time and ensemble averaging, 35 have been developed for an array of experimental observables measured for native, transition, intermediate, and unfolded states. 17,[36][37][38][39][40][41][42] One of the challenges in using replica-averaged structural restraints in molecular dynamics simulations, however, is that while the experimentally-determined average values are known, the underlying distribution (i.e., ensembles of structures) from which they come are not. 19,37 There is thus an ambiguity arising from the fact that infinitely many distributions may exist with the given set of average values.…”

Assessing and refining molecular dynamics simulations of proteins with nuclear magnetic resonance data

“…There are many documented examples of this (Glättli and van Gunsteren 2004;Missimer et al 2010;Allison et al 2011Allison et al , 2012Eichenberger et al 2012;Niggli et al 2012), including several in which the majority of the NMR data are equally compatible with the folded or unfolded states (Daura et al 1999(Daura et al , 2001Peter et al 2003;Zagrovic and van Gunsteren 2006). This insensitivity of NMR observables to the shape of the underlying probability distribution of structural properties has been demonstrated analytically (Bürgi et al 2001) and is illustrated in the upper panel of Fig.…”

The Structure of Neuronal Calcium Sensor-1 in Solution Revealed by Molecular Dynamics Simulations

“…The MD technique has been assessed as a reliable tool to refine experimental structures [23]–[26]. Thus, two long MD simulations at the temperature of 310 K were performed starting from the X-ray structure (MD-XR) and the NMR structure (MD-NMR).…”