Computational and theoretical approaches for studies of a lipid recognition protein on biological membranes

Abstract

Many cellular functions, including cell signaling and related events, are regulated by the association of peripheral membrane proteins (PMPs) with biological membranes containing anionic lipids, e.g., phosphatidylinositol phosphate (PIP). This association is often mediated by lipid recognition modules present in many PMPs. Here, I summarize computational and theoretical approaches to investigate the molecular details of the interactions and dynamics of a lipid recognition module, the pleckstrin homology (PH) domain, on biological membranes. Multiscale molecular dynamics simulations using combinations of atomistic and coarse-grained models yielded results comparable to those of actual experiments and could be used to elucidate the molecular mechanisms of the formation of protein/lipid complexes on membrane surfaces, which are often difficult to obtain using experimental techniques. Simulations revealed some modes of membrane localization and interactions of PH domains with membranes in addition to the canonical binding mode. In the last part of this review, I address the dynamics of PH domains on the membrane surface. Local PIP clusters formed around the proteins exhibit anomalous fluctuations. This dynamic change in protein-lipid interactions cause temporally fluctuating diffusivity of proteins, i.e., the short-term diffusivity of the bound protein changes substantially with time, and may in turn contribute to the formation/dissolution of protein complexes in membranes.

Keywords: Peripheral membrane protein; molecular dynamics simulation; phosphatidylinositol phosphate; pleckstrin homology domain; protein-lipid interaction.

Figure 1

The PH domain/membrane simulation pipeline for a variety of PH domains [28]. (A) Snapshot of a selected simulation demonstrating the localization of the general receptor of phosphoinositides 1 (GRP1) PH domain to the lipid bilayer. Alignment of the PH/PIP complexes derived from the simulation approach (with PH domains in yellow and PIP molecules in cyan/red/bronze/silver) with the corresponding crystal structures (PH domains and PIP both in blue). These complexes were obtained from the maxima in the density maps shown in (B). (B) Normalized density map of the GRP1 PH domain (zz component of rotational matrix versus distance between a PH domain and the lipid membrane). The ensemble used for the calculation are 25 1 μs for CG-MD and 2 1 μs for AT-MD. (C) Normalized average number of contacts between the GRP1 PH domain and PIPs. The light blue colors represent the experimental contacts observed in the crystal structure. (D) PH/PIP complexes derived from simulation.

Figure 2

Cluster of PIP lipids around PH domains [51]. (A) Snapshots of the membrane-bound DAPP1 PH domain. The leaflet (cyan) where the PH domain binds is shown. PIP₂ and PIP₃ lipids are shown as pink and gray, respectively. (B) Time series of the number of PIP₂ and PIP₃ molecules around the PH domain. (C) Ensemble-averaged PSDs of the number of PIP₃ molecules around the PH domain. The different colored lines represent different measurement times, and their power spectra coincide without fitting.

Figure 3

Diffusion process of the DAPP1 PH domain [61]. (A) The TAMSDs of 97 trajectories of the PH domain on the membrane surface. The measurement time for each trajectory t is 8 μs. The inset shows the mean of TAMSDs. (B) Snapshots of the PH domain in the many PIP bound state (left) and few PIP bound state (right). The PH domain, lipid bilayer, and bound PIP are colored yellow, silver, and cyan/red, respectively. (C) Lateral trajectory of PH domain on the membrane surface. Colors of the trajectory correspond to each state in (D). The black triangles indicate the start and end points. (D) Time series of the short-time diffusivity and the time-averaged number of bound PIPs in each diffusive state.