Molecular Dynamics Simulations Of Interactions Between Two-dimensional Nanomaterials And Proteins

Two-dimensional(2D)nanomaterials(NMs),such as graphene and MoS2,have attracted great attention in a wide range of biomedical applications lately.There are also growing concerns about the biosafety of these NMs.Therefore,a deeper understanding of interactions between NMs and proteins can assist rational usage of NMs in biomedical applications.Molecular dynamics(MD)simulations have been widely adopted to illustrate these interactions.Complementary to experiments,MD simulations can not only reveal mechanisms of these interaction,but also provide nanoscale information which might not be observed easily in experiments.Thus,by employing MD simulation methods,we studied the interactions between these two NMs and some representative proteins in this thesis.Firstly,we systematically investigated the interaction mechanisms of MoS2 nanosheet with Calmodulin using all-atom MD simulations.Calmodulin is present in all eukaryotic cells,mediating Ca2+-dependent signaling.Upon binding Ca2+,calmodulin changes its conformation to form complexes with a diverse array of target proteins.We found that Calmodulin exhibited considerable structural damage upon its adsorption onto the MoS2 nanosheet surface.Furthermore,MoS2 nanosheet could hinder Ca2+-free calmodulin from adjusting conformation and thus the protein was not regulated by calcium ions.The strong van der Waals(vdW)and hydrophobic interaction between MoS2 and calmodulin were the main driving forces that inhibited protein dynamics.Our findings indicated that the nanotoxicity of MoS2 to the protein arose not only from the denaturing capability to the protein,but also from impacts on the dynamic property.Secondly,we used all-atom MD simulations to study polyglutamine(polyQ)adsorption onto graphene and MoS2 nanosheet.There is a strong negative correlation between the polyglutamine(polyQ)domain length(Q-length)in the intrinsically disordered Huntingtin protein(Htt)exon-1 and the age of onset of Huntington's disease(HD).PolyQ with Q-length longer than 40 has the propensity of forming very compact aggregate structures,leading to HD at full penetrance.We investigated two poly glutamine-lengths,22(Q22,healthy Q-length)and 46(Q46,typical Q-length associated with HD at full penetrance)to determine if the binding mechanism of the polyQ on these nanosheets is Q-length dependent.We found that Q22 exhibited a similar binding mode on both graphene and MoS2 surfaces(with graphene showing a slightly stronger effect)regardless of its initial configuration-the final conformation of Q22 was fully extended.In contrast,initially collapsed Q46 remains mostly collapsed within our simulation time on both nanosheets even though they do provide some "stretching" to Q46 as well.Further energetic and hydrogen bonding analyses indicated that the difference in Q22 vs.Q46 binding conformations was determined by the competition between polyQ internal interactions(mainly intra-hydrogen-bonds)and polyQ-nanosheet interactions.Our results present distinct Q-length specific behavior of the polyQ domain upon binding to two types of 2D-nanomaterials which may lead to future potential applications in diagnoses and therapeutics for Huntington's disease.Overall,we used all-atom MD simulations to investigate interactions between different 2D NMs and two representative proteins in detail.We hope these studies can provide insights for deeper understanding of NM-protein interactions,which might help facilitate potential biomedical applications of these important NMs.