title: A molecular dynamics study of the binary complexes of APP, JIP1, and the cargo binding domain of KLC.
abstract: Mutations in the amyloid precursor protein (APP) are responsible for the formation of amyloid-β peptides. These peptides play a role in Alzheimer's and other dementia-related diseases. The cargo binding domain of the kinesin-1 light chain motor protein (KLC1) may be responsible for transporting APP either directly or via interaction with C-jun N-terminal kinase-interacting protein 1 (JIP1). However, to date there has been no direct experimental or computational assessment of such binding at the atomistic level. We used molecular dynamics and free energy estimations to gauge the affinity for the binary complexes of KLC1, APP, and JIP1. We find that all binary complexes (KLC1:APP, KLC1:JIP1, and APP:JIP1) contain conformations with favorable binding free energies. For KLC1:APP the inclusion of approximate entropies reduces the favorability. This is likely due to the flexibility of the 42-residue APP protein. In all cases we analyze atomistic/residue driving forces for favorable interactions. Proteins 2017; 85:221-234. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Chemistry, Gottwald Center for the Sciences, University of Richmond, Richmond, Virgina, 23173.
authors.forename: Cooper A
authors.initials: CA
authors.lastname: Taylor
authors.affiliation: Department of Chemistry, Truman State University, Kirksville, Missouri, 63501.
authors.forename: Bill R
authors.initials: BR
authors.lastname: Miller
authors.affiliation: Department of Chemistry, Gottwald Center for the Sciences, University of Richmond, Richmond, Virgina, 23173.
authors.forename: Soleil S
authors.initials: SS
authors.lastname: Shah
authors.affiliation: Department of Chemistry, Gottwald Center for the Sciences, University of Richmond, Richmond, Virgina, 23173.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Parish
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry*; D020816:Amino Acid Motifs; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry*; D001665:Binding Sites; D006801:Humans; D016547:Kinesins; D007700:Kinetics; D008869:Microtubule-Associated Proteins / Q000737:chemistry*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: C545487:APP protein, human; D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; C000715688:KLC1 protein, human; C490666:MAPK8IP1 protein, human; D008869:Microtubule-Associated Proteins; D016547:Kinesins
keywords: APP; Alzheimer's disease; JIP1; KLC1; amyloid precursor protein; c-jun amino-terminal kinase-interacting protein 1; kinesin; kinesin light chain 1; molecular dynamics; protein-protein interactions