Presentation Title: Simulation-assisted Discovery of Membrane Targeting Nanomedicine
Prof. Huajian Gao presented this talk in the webinar on Nanomedicine, Nanomaterials and Nanotechnology organized by Vebleo
Authors: Huajian Gao1,2,3, Guijin Zou2, Yue Liu3
Affiliation:
1Nanyang Technological University, Singapore 639798, Singapore
2Institute of High Performance Computing, A*STAR, Singapore 138632, Singapore
3Brown University, Providence, RI 02912, USA
Biography
Huajian Gao received his B.S. degree from Xian Jiaotong University in 1982, and his M.S. and Ph.D. degrees in Engineering Science from Harvard University in 1984 and 1988, respectively. He served on the faculty of Stanford University between 1988 and 2002, where he was promoted to Associate Professor with tenure in 1994 and to Full Professor in 2000.
Prof. Huajian Gao served as Director at the Max Planck Institute for Metals Research between 2001 and 2006, and then as Walter H. Annenberg Professor of Engineering at Brown University from 2006-2019. At present, he is one of 5 Distinguished University Professors at Nanyang Technological University and Scientific Director of Institute of High Performance Computing in Singapore.
Professor Huajian Gao’s research has been focused on the understanding of basic principles that control mechanical properties and behaviors of materials in both engineering and biological systems. He is the Editor-in-Chief of Journal of the Mechanics and Physics of Solids, the flagship journal of his field. He has been elected to memberships in US National Academy of Sciences, US National Academy of Engineering, American Academy of Arts and Sciences, German National Academy of Sciences, Chinese Academy of Sciences and Academia Europaea.
Prof. Huajian Gao has also received numerous awards and honors, including the John Simon Guggenheim Fellowship, the Rodney Hill Prize in Solid Mechanics from the International Union of Theoretical and Applied Mechanics, the William Prager Medal from Society of Engineering Science, the Nadai Medal from American Society of Mechanical Engineers and the Theodor von Karman Medal from American Society of Civil Engineers.
Abstract
The COVID-19 pandemic has brought infectious diseases again to the forefront of global public health concerns. Here, we discuss some recent work on simulation-assisted discovery of membrane targeting nanomedicine to counter increasing antimicrobial resistance and potential application of similar ideas to the current pandemic. A recent report led by the world health organization (WHO) warned that 10 million people worldwide could die of bacterial infections each year by 2050.
To avert the crisis, membrane targeting antibiotics are drawing increasing attention due to their intrinsic advantage of low resistance development. In collaboration with a number of experimental groups, we show examples of simulation-assisted discovery of molecular agents capable of selectively penetrating and aggregating in bacterial lipid membranes, causing membrane permeability/rupture. Through systematic all-atom molecular dynamics simulations and free energy analysis, we demonstrate that the membrane activity of the molecular agents correlates with their ability to enter, perturb and permeabilize the lipid bilayers.
Further study on different cell membranes demonstrates that the selectivity results from the presence of cholesterol in mammalian but not in bacterial membranes, as the cholesterol can condense the hydrophobic region of membrane, preventing the penetration of the molecular agents. Following the molecular penetration, we establish a continuum theory and derive the energetic driving force for the domain aggregation and pore growth on lipid membrane. We show that the energy barrier to membrane pore formation can be significantly lowered through molecular aggregation on a large domain with intrinsic curvature and a sharp interface.
The theory is consistent with experimental observations and validated with coarse-grained molecular dynamics simulations of molecular domain aggregation leading to pore formation in a lipid membrane. The mechanistic modelling and simulation provide some fundamental principles on how molecular antimicrobials interact with bacterial membranes and damage them through domain aggregation and pore formation. For treating viral infections and cancer therapy, we discuss potential size- and lipid-type-based selectivity principles for developing membrane active nanomedicine. These studies suggest a general simulation-assisted platform to accelerate discovery and innovation in nanomedicine against infectious diseases.
Graphical Abstract
This talk was delivered in the webinar organized by Vebleo