TY - JOUR

T1 - Computational Approaches to Explore Bacterial Toxin Entry into the Host Cell

AU - Pezeshkian, Weria

AU - Shillcock, Julian C.

AU - Ipsen, John H.

PY - 2021/7/28

Y1 - 2021/7/28

N2 - Many bacteria secrete toxic protein complexes that modify and disrupt essential processes in the infected cell that can lead to cell death. To conduct their action, these toxins often need to cross the cell membrane and reach a specific substrate inside the cell. The investigation of these protein complexes is essential not only for understanding their biological functions but also for the rational design of targeted drug delivery vehicles that must navigate across the cell membrane to deliver their therapeutic payload. Despite the immense advances in experimental techniques, the investigations of the toxin entry mechanism have remained challenging. Computer simulations are robust complementary tools that allow for the exploration of biological processes in exceptional detail. In this review, we first highlight the strength of computational methods, with a special focus on all-atom molecular dynamics, coarse-grained, and mesoscopic models, for exploring different stages of the toxin protein entry mechanism. We then summarize recent developments that are significantly advancing our understanding, notably of the glycolipid-lectin (GL-Lect) endocytosis of bacterial Shiga and cholera toxins. The methods discussed here are also applicable to the design of membrane-penetrating nanoparticles and the study of the phenomenon of protein phase separation at the surface of the membrane. Finally, we discuss other likely routes for future development.

AB - Many bacteria secrete toxic protein complexes that modify and disrupt essential processes in the infected cell that can lead to cell death. To conduct their action, these toxins often need to cross the cell membrane and reach a specific substrate inside the cell. The investigation of these protein complexes is essential not only for understanding their biological functions but also for the rational design of targeted drug delivery vehicles that must navigate across the cell membrane to deliver their therapeutic payload. Despite the immense advances in experimental techniques, the investigations of the toxin entry mechanism have remained challenging. Computer simulations are robust complementary tools that allow for the exploration of biological processes in exceptional detail. In this review, we first highlight the strength of computational methods, with a special focus on all-atom molecular dynamics, coarse-grained, and mesoscopic models, for exploring different stages of the toxin protein entry mechanism. We then summarize recent developments that are significantly advancing our understanding, notably of the glycolipid-lectin (GL-Lect) endocytosis of bacterial Shiga and cholera toxins. The methods discussed here are also applicable to the design of membrane-penetrating nanoparticles and the study of the phenomenon of protein phase separation at the surface of the membrane. Finally, we discuss other likely routes for future development.

KW - computational methods

KW - molecular dynamics simulations

KW - coarse-grained simulations

KW - bacterial toxin

KW - membrane remodeling

KW - MULTISCALE MOLECULAR-DYNAMICS

KW - CHOLERA-TOXIN

KW - TRANSLOCATION DOMAIN

KW - FORCE-FIELD

KW - MEMBRANE

KW - BINDING

KW - SIMULATIONS

KW - MODEL

KW - GM1

KW - ASSOCIATION

U2 - 10.3390/toxins13070449

DO - 10.3390/toxins13070449

M3 - Review

C2 - 34203472

VL - 13

JO - Toxins

JF - Toxins

SN - 0142-8535

IS - 7

M1 - 449

ER -