Systematic multiscale simulation of membrane protein systems

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Current multiscale simulation approaches for membrane protein systems vary depending on their degree of connection to the underlying molecular scale interactions. Various approaches have been developed that include such information into coarse-grained models of both the membrane and the proteins. By contrast, other approaches employ parameterizations obtained from experimental data. Mesoscopic models operate at larger scales and have also been employed to examine membrane remodeling, protein inclusions, and ion channel gating. When bridged together such that molecular-level information is propagated between the different scales, a systematic multiscale methodology for membrane protein systems can be achieved.

Introduction

Biomolecular systems consisting of membranes interacting with either embedded or bound proteins (which, from this point forward, will be referred to as membrane protein systems) represent an important challenge in the field of biomolecular simulation. The large length and time scales involved in these systems have motivated the development of novel coarse-grained (CG) and mesoscopic simulation approaches [1] to complement all-atom molecular dynamics (MD) simulation. Previous reviews in this journal have examined aspects of multiscale simulation in complex biomolecular systems [2, 3, 4, 5], while other articles have reviewed the current state of large scale MD and CG simulations of self-assembly [6], and the upper length scale limits of all atom MD simulation [7]. Excellent reviews examining the overall challenge of simulating membrane proteins can be found in Refs. [8, 9], and a review of current MD protein and lipid force fields has recently appeared [10].

The focus of this review is on the ways in which molecular-level interactions can be incorporated into the systematic multiscale modeling of membrane protein systems. This focus is different from approaches based on parameterization of CG or mesoscopic models from experimental or other ‘knowledge-based’ modeling concepts. The next section will describe, in a general context, how molecular-level information can be incorporated and bridged into multiscale descriptions of membrane protein systems. Subsequent sections in this review will describe various recent CG and mesoscopic approaches, and how they each incorporate this important concept into their underlying methodologies.

Section snippets

Systematic multiscale simulation of membrane protein systems

The two main components of a multiscale simulation methodology for membrane protein systems are CG simulation (see Refs. [1, 2, 3, 4, 5] for examples and reviews) and mesoscopic and/or continuum approaches [11, 12, 13, 14••, 15, 16, 17]. A CG model is one where at least three heavy atoms are combined into one single CG site and, as a result, some degree of molecular-level structure is retained. With CG simulation, the typical computational speedup can be from 10 to 1000 times faster than

The multiscale coarse-graining methodology

The MS-CG methodology [22, 23, 24••, 25, 26] provides a rigorous bottom-up theoretical framework in which to construct CG models from the underlying molecular scale forces, and thus it provides a direct route for path (1) in Figure 1. It shares with other complementary inverse CG approaches [33, 34] the ability to directly incorporate atomistic MD simulation data into the resultant CG force field. Further development of the MS-CG method has formalized the variational aspect of the approach and

Parameterized ‘top-down’ CG force fields for membrane protein systems

Force fields such as the MARTINI CG force field [27, 28••, 29, 30•, 31] were originally designed for CG simulations of lipid bilayers [27] and have recently been extended to proteins [28••]. Variants by Sansom and coworkers [29, 30•] and Schulten and coworkers [31] have also been developed. The philosophy of the MARTINI approach differs substantially from the MS-CG method [24••, 25, 26] and inverse coarse-graining techniques [33, 34] in that the parameterization of the model employs certain

Mesoscopic simulation

As shown in Figure 1 the important endpoint of the overall multiscale simulation approach for membrane protein systems is the mesoscopic model (image (c)). The work of Brown and coworkers involving the development of consistent elastic theories for membrane protein inclusions [13, 14••] is important in this regard. In this approach [13, 14••] a generic CG membrane simulation is used in order to validate various advanced continuum elastic membrane models; a distinct Gaussian curvature

Conclusions and outlook

This article has described strategies to develop a systematic multiscale simulation methodology for membrane protein simulations (cf. Figure 1). A number of current and promising CG and mesoscopic approaches have been surveyed. In terms of CG methods, the MS-CG approach offers a systematic and rigorous route to develop the critical CG component of membrane protein systems where detailed molecular level information is propagated from bottom-up in scale to the CG level. However, the MS-CG

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgement

This research was supported by the National Institutes of Health (R01-GM063796).

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