Efficient Exploration of Membrane-Associated Phenomena at Atomic Resolution

Abstract

Biological membranes constitute a critical component in all living cells. In addition to providing a conducive environment to a wide range of cellular processes, including transport and signaling, mounting evidence has established active participation of specific lipids in modulating membrane protein function through various mechanisms. Understanding lipid-protein interactions underlying these mechanisms at a sufficiently high resolution has proven extremely challenging, partly due to the semi-fluid nature of the membrane. In order to address this challenge computationally, multiple methods have been developed, including an alternative membrane representation termed HMMM (highly mobile membrane mimetic) in which lateral lipid diffusion has been significantly enhanced without compromising atomic details. The model allows for efficient sampling of lipid-protein interactions at atomic resolution, thereby significantly enhancing the effectiveness of molecular dynamics simulations in capturing membrane-associated phenomena. In this review, after providing an overview of HMMM model development, we will describe briefly successful application of the model to study a variety of membrane processes, including lipid-dependent binding and insertion of peripheral proteins, the mechanism of phospholipid insertion into lipid bilayers, and characterization of optimal tilt angle of transmembrane helices. We conclude with practical recommendations for proper usage of the model in simulation studies of membrane processes.

The cellular membrane as a mediator for small molecule interaction with membrane proteins

“…The particle count can be reduced even further by removing the explicit membrane atoms altogether, replacing them with an implicit membrane model in which the effect of the membrane is applied as a continuum with varying dielectric [69], again enabling longer simulations. Membrane representations that increase the diffusion constant of the lipids [70] by making them shorter and adding an organic solvent to fill the void have also been developed [71], which accelerates the kinetics of insertion processes [72] while preserving the energetics and specificity of a conventional membrane representation at the membrane periphery [73]. While each of these methods has their advantages, they make sacrifices in the accuracy of the molecular interactions; hence, the gold standard for MD simulation remains at the fully atomic scale.…”

“…Embedding proteins into such complex membranes further exacerbates the sampling problem due to increased viscosity, yielding protein structures that exhibit dynamics very different from their solution form. These scenarios may be alleviated by alternative methods that enhance sampling, e.g., reduced representations of the membrane as done in the HMMM model [70, 71], coarse-grained membrane models [67], or implicit membrane models for protein complex formation [225–227], and will likely be required in future studies.…”

Atomic-level description of protein–lipid interactions using an accelerated membrane model

“…1) [73, 74]. The short-tailed, yet fully atomistic lipids, placed at the organic solvent/water interface to capture the chemistry inherent in protein-lipid interactions, have a self-diffusion constant that is at least an order of magnitude higher than conventional lipids [45, 74]. As a result, insertion processes on the membrane interface will be significantly accelerated [75] while accurately reproducing the energetics of molecular interactions at the interface [76].…”

Challenges in structural approaches to cell modeling

“…Recently, Tajkhorshid and coworkers developed the highly mobile membrane-mimetic (HMMM) model with accelerated lipid motion by replacing the lipid tails with small organic molecules [187]. The HMMM model provides accelerated lipid diffusion by 1-2 orders of magnitude, and is particularly useful in studying membrane-protein associations [188, 189]. …”