Open AccessPositive allosteric modulators of lecithin: Cholesterol acyltransferase adjust the orientation of the membrane-binding domain and alter its spatial free energy profile
Author(s) -
Akseli Niemelä,
Artturi Koivuniemi
Publication year - 2021
Publication title -
plos computational biology/plos computational biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.628
H-Index - 182
eISSN - 1553-7358
pISSN - 1553-734X
DOI - 10.1371/journal.pcbi.1008426
Subject(s) - allosteric regulation , sterol o acyltransferase , molecular dynamics , biophysics , chemistry , phospholipid , umbrella sampling , docking (animal) , binding site , allosteric enzyme , lecithin , acyltransferase , biochemistry , membrane , cholesterol , biology , enzyme , computational chemistry , lipoprotein , medicine , nursing
Lecithin:cholesterol acyltransferase protein (LCAT) promotes the esterification reaction between cholesterol and phospholipid-derived acyl chains. Positive allosteric modulators have been developed to treat LCAT deficiencies and, plausibly, also cardiovascular diseases in the future. The mechanism of action of these compounds is poorly understood. Here computational docking and atomistic molecular dynamics simulations were utilized to study the interactions between LCAT and the activating compounds. Results indicate that all drugs bind to the allosteric binding pocket in the membrane-binding domain in a similar fashion. The presence of the compounds in the allosteric site results in a distinct spatial orientation and sampling of the membrane-binding domain (MBD). The MBD’s different spatial arrangement plausibly affects the lid’s movement from closed to open state and vice versa , as suggested by steered molecular dynamics simulations.