Predicting Membrane-Active Peptide Dynamics in Fluidic Lipid Membranes

TY - CHAP

T1 - Predicting Membrane-Active Peptide Dynamics in Fluidic Lipid Membranes

AU - Chen, Charles H.

AU - Pepper, Karen

AU - Ulmschneider, Jakob P.

AU - Ulmschneider, Martin B.

AU - Lu, Timothy K.

N1 - Funding Information: This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) under Award Number U19AI142780. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors thank Kalina Hristova at Johns Hopkins University, William Wimley at Tulane University, Alexey Ladokhin at University of Kansas Medical Center, Jochen Bürck at Karlsruhe Institute of Technology, Nykola Jones at Aarhus University, Katherine Tripp at Johns Hopkins University, Gregory Wiedman at Seton Hall University, Sarah Kim at Duke University, Evan Troendle at King’s College London, and Yukun Wang at Yale University for valuable discussions about the experimental setups and simulations. Publisher Copyright: © 2022, The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.

PY - 2022

Y1 - 2022

N2 - Understanding the interactions between peptides and lipid membranes could not only accelerate the development of antimicrobial peptides as treatments for infections but also be applied to finding targeted therapies for cancer and other diseases. However, designing biophysical experiments to study molecular interactions between flexible peptides and fluidic lipid membranes has been an ongoing challenge. Recently, with hardware advances, algorithm improvements, and more accurate parameterizations (i.e., force fields), all-atom molecular dynamics (MD) simulations have been used as a “computational microscope” to investigate the molecular interactions and mechanisms of membrane-active peptides in cell membranes (Chen et al., Curr Opin Struct Biol 61:160–166, 2020; Ulmschneider and Ulmschneider, Acc Chem Res 51(5):1106–1116, 2018; Dror et al., Annu Rev Biophys 41:429–452, 2012). In this chapter, we describe how to utilize MD simulations to predict and study peptide dynamics and how to validate the simulations by circular dichroism, intrinsic fluorescent probe, membrane leakage assay, electrical impedance, and isothermal titration calorimetry. Experimentally validated MD simulations open a new route towards peptide design starting from sequence and structure and leading to desirable functions.

AB - Understanding the interactions between peptides and lipid membranes could not only accelerate the development of antimicrobial peptides as treatments for infections but also be applied to finding targeted therapies for cancer and other diseases. However, designing biophysical experiments to study molecular interactions between flexible peptides and fluidic lipid membranes has been an ongoing challenge. Recently, with hardware advances, algorithm improvements, and more accurate parameterizations (i.e., force fields), all-atom molecular dynamics (MD) simulations have been used as a “computational microscope” to investigate the molecular interactions and mechanisms of membrane-active peptides in cell membranes (Chen et al., Curr Opin Struct Biol 61:160–166, 2020; Ulmschneider and Ulmschneider, Acc Chem Res 51(5):1106–1116, 2018; Dror et al., Annu Rev Biophys 41:429–452, 2012). In this chapter, we describe how to utilize MD simulations to predict and study peptide dynamics and how to validate the simulations by circular dichroism, intrinsic fluorescent probe, membrane leakage assay, electrical impedance, and isothermal titration calorimetry. Experimentally validated MD simulations open a new route towards peptide design starting from sequence and structure and leading to desirable functions.

KW - Membrane-active peptides

KW - Molecular dynamics simulations

KW - Pore formation

KW - Protein design

KW - Protein folding

UR - https://www.scopus.com/pages/publications/85126991396

U2 - 10.1007/978-1-0716-1855-4_6

DO - 10.1007/978-1-0716-1855-4_6

M3 - Chapter

C2 - 35298811

AN - SCOPUS:85126991396

T3 - Methods in Molecular Biology

SP - 115

EP - 136

BT - Methods in Molecular Biology

PB - Humana Press Inc

ER -