Quantifying and Enhancing the Statistical Convergence of Equilibrium and Non-equilibrium Properties in Molecular Simulations of Proteins, Peptides, and Amino Acid Side Chain Analogs Embedded in Lipid Bilayers

Atomistic molecular simulations provide high-resolution structural and dynamic characterizations of small molecules, peptides, and proteins interacting with biological membranes. Here I use new methods and massively repeated computer simulations to critically examine the statistical convergence of equilibrium and non-equilibrium properties in molecular simulations of three types of solute in hydrated phospholipid bilayers: amino acid side-chain analogs, the intrinsically disordered antimicrobial peptide indolicidin, and the bacterial magnesium channel CorA. This thesis is as much a journey to discover what one can learn from simulations by quantifying their sampling errors as it is a quest for convergence using massive computational resources and enhanced sampling techniques. I first evaluate the convergence of the standard binding free energy for the reversible bilayer insertion of amino acid side-chain analogs and indolicidin. I identify rare and abrupt transitions in bilayer structure resulting from slow reorganization of intermolecular ionic interactions, which constitute hidden sampling barriers that limit the rate of convergence of equilibrium properties and result in systematic sampling errors. Next, I introduce three new generalized ensemble sampling algorithms and show that they dramatically enhance the efficiency of quantifying free energy profiles for solute insertion across a lipid bilayer. I employ one of these methods with a novel analysis tool to accurately predict the amount of additional simulation time required to attain converged estimates of equilibrium properties – something that has never before been accomplished. Finally, I examine the functional hydration of a hydrophobic gate by comparing hundreds of simulations in which the regulatory sites of the CorA magnesium channel are either fully occupied or empty. In the absence of regulatory ions, water penetrates more readily into a 1.5-nm-long channel constriction that is dehydrated in all available crystal structures. These wetting transitions involve more water, and the resulting hydration is more stable, when regulatory ions are absent. Furthermore, this hydration reduces the free energy barrier to the conduction of magnesium. While many of the ensemble-averaged values presented in this thesis have converged, intra-ensemble comparisons indicate incomplete convergence of the constituent simulations. Because my microsecond-scale constituent simulations are long by contemporary standards, I conclude that the difficulty of attaining convergence for bilayer-embedded solutes is drastically underestimated in the literature.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.