Folding is Not Required for Bilayer Insertion: Replica Exchange Simulations of an a-Helical Peptide with an Explicit Lipid Bilayer

Hugh Nymeyer; Thomas B. Woolf; Angel E. Garcia

Home/Archive/arXiv

arXiv · q-bio/0411001

Folding is Not Required for Bilayer Insertion: Replica Exchange Simulations of an a-Helical Peptide with an Explicit Lipid Bilayer

Hugh Nymeyer·Thomas B. Woolf·Angel E. Garcia

View original source ↗Read source document ↗Export metadata ↓

Abstract

We implement the replica exchange molecular dynamics algorithm to study the interactions of a model peptide (WALP-16) with an explicitly represented DPPC membrane bilayer. We observe the spontaneous, unbiased insertion of WALP-16 into the DPPC bilayer and its folding into an a-helix with a trans-bilayer orientation. We observe that the insertion of the peptide into the DPPC bilayer precedes secondary structure formation. Although the peptide has some propensity to form a partially helical structure in the interfacial region of the DPPC/water system, this state is not a productive intermediate but rather an off-pathway trap for WALP-16 insertion. Equilibrium simulations show that the observed insertion/folding pathway mirrors the potential of mean force (PMF). Calculation of the enthalpic and entropic contributions to this PMF show that the surface bound conformation of WALP-16 is significantly lower in energy than other conformations, and that the insertion of WALP-16 into the bilayer without regular secondary structure is enthalpically unfavorable by 5-10 kcal/mol/residue. The observed insertion/folding pathway disagrees with the dominant conceptual model, which is that a surface bound helix is an obligatory intermediate for the insertion of a-helical peptides into lipid bilayers. In our simulations, the observed insertion/folding pathway is favored because of a large (> 100 kcal/mol) increase in system entropy that occurs when the unstructured WALP-16 peptide enters the lipid bilayer interior. The insertion/folding pathway that is lowest in free energy depends sensitively on the near cancellation of large enthalpic and entropic terms. This suggests that intrinsic membrane peptides may have a diversity of insertion/folding behaviors depending on the exact system of peptide and lipid under consideration.

Explore related subjects

q-bio.BM

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Hugh Nymeyer, Thomas B. Woolf, Angel E. Garcia. 2004-10-29. Folding is Not Required for Bilayer Insertion: Replica Exchange Simulations of an a-Helical Peptide with an Explicit Lipid Bilayer. https://arxiv.org/abs/q-bio/0411001

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related papers

arXiv2026

PocketVE: Stable and Property-Guided Structure-Based Drug Design with Variance-Exploding Diffusion

Protein-conditioned 3D molecule generation is a central challenge in structure-based drug design, requiring a balance between pocket compatibility, molecular properties, and physical geometry. We propose \textbf{PocketVE}, a protein-pocket-conditioned variance-exploding (VE) diffusion framework that couples stable coordinate denoising with inference-time property guidance. Specifically, PocketVE combines an EDM-style training and sampling setup for 3D denoising, classifier-free guidance for multi-property steering without external property classifiers, and adaptive protein perturbation as a training-time pocket regularizer. Evaluated on CrossDocked2020 under the GenBench3D protocol, PocketVE improves Valid$_{3\text{D}}$ from 58.6 to 80.6 and reduces strain energy from 457.4 to 127.9 relative to its TAGMol architectural baseline, while retaining competitive docking and molecular-property scores under moderate guidance. A guidance-scale study shows that moderate guidance gives a favorable balance between target-related objectives and geometric quality, whereas stronger guidance can degrade geometry and distributional fidelity. Pocket-permutation and PoseCheck diagnostics further support pocket-specific spatial compatibility with reduced steric conflicts. Overall, the results suggest that geometric stability and inference-time property guidance should be considered as coupled design objectives.

q-bio.BM↗

arXiv2026

In Vivo Length Distributions as Mechanistic Fingerprints of Pathological Protein Aggregation

Modern imaging techniques can resolve individual pathological protein aggregates in postmortem human samples, providing detailed measurements of aggregate size distributions that are inaccessible with conventional bulk approaches. These distributions represent mechanistic fingerprints of the microscopic processes that generated the observed pathology, but extracting this mechanistic information requires a quantitative theoretical framework. Here, we develop the mathematical tools needed to interpret aggregate length distributions in living systems, where aggregate growth competes with active removal. We show that, across a class of models, the length distribution of sufficiently large aggregates approaches a geometric decay. Crucially, the decay rate is determined by the balance between aggregate elongation and removal, providing a direct quantitative readout of these competing processes from a single time point measurement. This enables mechanistic comparisons between healthy and diseased human samples without requiring longitudinal measurements of aggregate dynamics. We further analyse how additional aggregation and removal processes modify the observed length distributions. Together, these results establish the mathematical foundations and tools to use aggregate length distributions as an experimentally accessible route for inferring microscopic aggregation dynamics directly from human tissue.

q-bio.BM↗

arXiv2026

Decoding enzyme-substrate interaction topology reveals principles underlying catalytic efficiency and mutational outcomes

The enzyme turnover number (kcat) defines catalytic efficiency and constrains quantitative models of metabolism, yet the molecular determinants governing kcat and its response to mutation remain poorly understood. Measurements are sparse and labor-intensive, and most computational approaches provide numerical predictions without explaining how enzyme-substrate interactions shape catalytic outcomes. A central challenge is therefore to identify the topological principles that determine where mutations act and how their functional outcomes are encoded within the enzyme-substrate interaction network. Here, we show that catalytic efficiency and mutational effects can be interpreted through enzyme-substrate interaction topology. We developed Interkcat, an interpretable bidirectional cross-attention framework that captures reciprocal coordination between protein residues and substrate atoms. Optimized on a unified benchmark, Interkcat achieves state-of-the-art predictive performance (R2 = 0.701). From its learned representations, we derive an Interaction Topology Score (ITS) that identifies sequence regions statistically enriched for mutation-sensitive sites without explicit structural inputs. We further demonstrate that higher-order topological features distinguish opposing mutational outcomes: lethal mutations disrupt coordinated networks, whereas activity-preserving or enhancing mutations retain sparse, globally organized coupling. These findings establish interaction topology as a unifying principle linking enzyme sequence, catalytic efficiency, and evolutionary perturbation.

q-bio.BM↗