Extension of a protein docking algorithm to membranes and applications to amyloid precursor protein dimerization

Abstract

Novel adjustments are introduced to the docking algorithm, DOCK/PIERR, for the purpose of predicting structures of transmembrane protein complexes. Incorporating knowledge about the membrane environment is shown to significantly improve docking accuracy. The extended version of DOCK/PIERR is shown to perform comparably to other leading docking packages. This membrane version of DOCK/PIERR is applied to the prediction of coiled-coil homodimer structures of the transmembrane region of the C-terminal peptide of amyloid precursor protein (C99). Results from MD simulation of the C99 homodimer in POPC bilayer and docking are compared. Docking results are found to capture key aspects of the homodimer ensemble, including the existence of three topologically distinct conformers. Furthermore, the extended version of DOCK/PIERR is successful in capturing the effects of solvation in membrane and micelle. Specifically, DOCK/PIERR reproduces essential differences in the homodimer ensembles simulated in POPC bilayer and DPC micelle, where configurational entropy and surface curvature effects bias the handedness and topology of the homodimer ensemble.

Structure of APP-C991–99 and implications for role of extra-membrane domains in function and oligomerization

“…It has further been noted that the membrane thickness can preferentially stabilize and environmentally select specific C99 dimer strucutres. [17,26–28] Beyond the hinge lies G 38 xxxA 42 , another glycine zipper motif often found in TM dimers,[18] important for C99 homodimerization. [29] The GxxxG repeat motif appears to facilitate C99 dimer formation in thicker membranes while the competing GxxxA motif supports dimers are most often observed in thinner membrane and micelle.…”

Structure of APP-C991-99and Implications for Role of Extra-Membrane Domains in Function and Oligomerization

“…It has further been noted that the membrane thickness can preferentially stabilize and environmentally select specific C99 dimer strucutres. [17,[26][27][28] Beyond the hinge lies G 38 xxxA 42 , another glycine zipper motif often found in TM dimers, [18] important for C99…”

“…The N-terminus of C99 almost certainly interacts with the nicastrin domain of γ-secretase. [35] Within the N-Loop domain, Ala point mutation of K 28 has a dramatic impact on APP processing, switching formation of Aβ 40 to Aβ 33 , implicating this turn in the γ-secretase interaction. [34] Residues 15 to 21 (LVFFAED of the N-Helix domain), sometimes referred to as the juxtamembrane (JM) region, is plays a role in inhibiting γ-secretase binding [36] and binding with cholesterol.…”

Integrative modeling of membrane-associated protein assemblies

“…Sampling and scoring might be coupled (scoring-driven sampling) or work as independent steps (sampling and then scoring). In the context of membrane protein docking, software such as Rosetta 32 , DOCK/PIERR 33 , and Memdock 34 include built-in specific protocols to model transmembrane domains using implicit membrane potentials. Besides RosettaMP 35 (for membrane protein design), none of the available membranespecific computational methods allow for an explicit representation of the lipid bilayer and, therefore, cannot harvest the topological information encoded in it.…”