Statistical Analysis of Ion Mobility Spectrometry. I. Unbiased and Guided Replica-Exchange Molecular Dynamics

Abstract

Achieving (bio)macromolecular structural assignment from the interpretation of ion mobility spectrometry (IMS) experiments requires successful comparison with computer modeling. Replica-exchange molecular dynamics simulations with suitable force fields not only offer a convenient framework to locate relevant conformations, especially in the case of multiple-funnel energy landscapes, but they are also well suited to statistical analyses. In the present paper, we discuss two extensions of the method used to improve its efficiency in the context of IMS. Two doubly-protonated polyalanines [RA 4 XA 4 K + 2H] 2+ with X=V and D appear as favorable cases for which the calculated collision cross-section distributions naturally agree with the measurements, providing reliable candidate structures. For these compounds, a careful consideration of other order parameters based on the weighted histogram method resolves several otherwise hidden underlying conformational families. In the case of a much larger peptide exhibiting bistability, assignment is more difficult but could be achieved by guiding the sampling with an umbrella potential using the square gyration radius as the biasing coordinate. Applied to triply protonated bradykinine, the two presented methods indicate that different conformations compatible with the measurements are very close in energy.

Linking molecular models with ion mobility experiments. Illustration with a rigid nucleic acid structure

“…Several enhanced sampling techniques allow the species to overcome energetic barriers and explore other conformational 5À on the Synapt G1 and (C) Reconstructed collision cross section distributions for the ion [(dTG 4 T) basins, for example simulated annealing molecular dynamics, [57][58][59][60] replica-exchange molecular dynamics [61][62][63] and adaptively biased molecular dynamics. [64,65] On the other hand, when the molecular system taken into account is too big, as for instance large multiprotein complexes (>500 kDa), all the aforementioned atomistic methods are still too computationally expensive, but some qualitative models can be built instead, such as (bead-type) coarse grained models. [37,[66][67][68][69] Force fields A possible pitfall intrinsic in classical MD simulations in gas phase is related to the use of force fields (FFs) that are presently parameterized based on high-level quantum calculations, but eventually tested and tuned in aqueous phase (with either explicit or implicit water models).…”

Statistical Analysis of Ion Mobility Spectrometry. II. Adaptively Biased Methods and Shape Correlations

“…Although increasingly successful for interpreting ion mobility measurements [4,5,8,24], conventional molecular dynamics simulations may also face difficulties in locating conformations compatible with experiments due to either intrinsic force field limitations, or insufficient sampling time [24]. One useful strategy to facilitate interpretation of IMS measurements consists in guiding the sampling toward the regions of experimental interest, using a dedicated order parameter that hopefully mimics the measured property.…”

“…One useful strategy to facilitate interpretation of IMS measurements consists in guiding the sampling toward the regions of experimental interest, using a dedicated order parameter that hopefully mimics the measured property. The collision cross section itself cannot be used actively in such MD simulations, because it is not an explicit function of the coordinates (no gradient is available), but the gyration radius turns out to be a reasonable approximation [24]. It should be stressed here that the biased MD approach does not aim at approximating the CCS by a geometrical quantity, but to take advantage of the relation between the CCS and the molecular structure in order to save computational time in the production of realistic candidate structures.…”

“…One straightforward biasing method uses a so-called umbrella potential, in which conformations with prescribed values of the order parameter are favored. However, locating conformations with prescribed values of the collision cross section was still a challenge with this approach, the parameters for the guiding potential having to be adjusted by trial and error [24].…”

“…Following our previous work [24], we have chosen to test these ideas on selected peptides for which experimental IMS data are available. Triply protonated bradykinin was recently found by the Clemmer group [27,28] to exhibit three distinct signatures in ion mobility spectrometry upon specific activation.…”