Paper Citing NAMD - Abstract
Shams, Hengameh; Golji, Javad; Garakani, Kiavash; Mofrad, Mohammad R. K.
Dynamic Regulation of alpha-Actinin's Calponin Homology Domains on F-Actin
BIOPHYSICAL JOURNAL, 110:1444-1455, MAR 29 2016
alpha-Actinin is an essential actin cross-linker involved in cytoskeletal organization and dynamics. The molecular conformation of alpha-actinin's actin-binding domain (ABD) regulates its association with actin and thus mutations in this domain can lead to severe pathogenic conditions. A point mutation at lysine 255 in human alpha-actinin-4 to glutamate increases the binding affinity resulting in stiffer cytoskeletal structures. The role of different ABD conformations and the effect of K255E mutation on ABD conformations remain elusive. To evaluate the impact of K255E mutation on ABD binding to actin we use all-atom molecular dynamics and free energy calculation methods and study the molecular mechanism of actin association in both wild-type a-actinin and in the K225E mutant. Our models illustrate that the strength of actin association is indeed sensitive to the ABD conformation, predict the effect of K255E mutation-based on simulations with the K237E mutant chicken alpha-actinin-and evaluate the mechanism of alpha-actinin binding to actin. Furthermore, our simulations showed that the calmodulin domain binding to the linker region was important for regulating the distance between actin and ABD. Our results provide valuable insights into the molecular details of this critical cellular phenomenon and further contribute to an understanding of cytoskeletal dynamics in health and disease.
