This proposal examines the efficiency and selectivity of peptide transport through biological membranes. Peptides are widely used in biology to permeate through target membranes. They transport material to specific cells as well as cell compartments. They are also used as defense mechanisms against other organisms such as antimicrobial peptides, or against malignant cells (anticancer peptides). The diversity and specificity of peptide functions make them an excellent target for a study that aims to deliver material (drugs) with razor sharp accuracy into a selected cell or a cell compartment. An interdisciplinary team was assembled to study peptide interactions with biological membranes that encompass expertise in molecular dynamics simulations of biological molecules, expertise in physical chemistry experiments on biological systems that are able to pinpoint the location and measure the dynamics of a diverse set of peptides passing through different types of membranes, and expertise in biological experiments of peptide permeation into living cells. The interdisciplinary team is needed because of the tremendous complexity of biological membranes that are made of thousands types of different phospholipid molecules, and many other components such as cholesterol molecules and trans- membrane proteins. This complexity is necessary for membrane function. Novel simulation and experimental tools are developed that will make it possible to compute, predict and measure the impact of membrane and peptide variation on permeability and function. Variations in selectivity of the plasma membranes of cancer and normal cells were already illustrated and will be further investigated to elucidate specificity of molecular mechanisms and offer design principles. This project is expected to shed light on the detailed mechanisms that control the efficiency and selectivity of peptide transport through biological membranes, as well as offer avenues to impact these mechanisms.

Public Health Relevance

This proposal examines the efficiency and selectivity of transport of peptides through biological membranes. Molecular dynamics simulations, physical chemistry experiments, and biological experiments on living cells will be used to determine mechanisms and design principles of peptide transport through membranes. The outcome will impact our understanding of precise material delivery to cells and cell compartments.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM111364-05
Application #
9965180
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Lyster, Peter
Project Start
2016-06-01
Project End
2024-08-31
Budget Start
2020-09-15
Budget End
2021-08-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Miscellaneous
Type
Organized Research Units
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78759
Fathizadeh, Arman; Elber, Ron (2018) Ion Permeation Through a Phospholipid Membrane: Transition State, Path Splitting, and Calculation of Permeability. J Chem Theory Comput :
Valentine, Mason L; Cardenas, Alfredo E; Elber, Ron et al. (2018) Physiological Calcium Concentrations Slow Dynamics at the Lipid-Water Interface. Biophys J 115:1541-1551
Elber, Ron; Bello-Rivas, Juan M; Ma, Piao et al. (2017) Calculating Iso-Committor Surfaces as Optimal Reaction Coordinates with Milestoning. Entropy (Basel) 19:
Shrestha, Rebika; Anderson, Cari M; Cardenas, Alfredo E et al. (2017) Direct Measurement of the Effect of Cholesterol and 6-Ketocholestanol on the Membrane Dipole Electric Field Using Vibrational Stark Effect Spectroscopy Coupled with Molecular Dynamics Simulations. J Phys Chem B 121:3424-3436