Molecular Dynamics Simulations Study On The Allosteric Regulation Mechanism Of Protein Tyrosine Phosphatase PTP1B And SHP2

The reversible protein tyrosine phosphorylation is an important regulation mechanism for eukaryotic organisms to regulate various physiological processes.The protein tyrosine phosphatase(PTPs)superfamily can coordinate with the protein tyrosine kinases(PTKs)to maintain the physiological balance of intracellular tyrosine phosphorylation.Although scientists have been studying the regulation mechanism of PTPs for a long time,it is challenging to study the regulation mechanism of PTPs by experimental methods.It is difficult for scientists to obtain the dynamic structure of PTPs under physiological conditions.With the rapid development of computer technology and simulation algorithms,molecular dynamics simulation has become an important method for studying protein structure and function.Molecular dynamics simulation can not only study the dynamic changes of protein conformation,but also obtain energy information accompanying protein conformation changes.Tyrosineprotein phosphatase non-receptor type 1(PTP1B)is the first protein tyrosine phosphatase discovered,and it has become an important reference enzyme for other protein tyrosine enzymes.SHP2 is a special member of PTPs superfamily and it has two unique SH2 domains.PTP1 B and SHP2 are the most representative members of PTPs superfamily.The study of the allosteric mechanism of PTP1 B and SHP2 can help us better understand the allosteric regulation mechanism of the PTPs superfamily.In this paper,molecular dynamics simulation methods are used to theoretically study the allosteric regulation mechanism of protein tyrosine phosphatase PTP1 B and SHP2.The main contents are as follows:1.Exploring the allosteric mechanism of tyrosine-protein phosphatase non-receptor type 1 by molecular dynamics simulationsTyrosine-protein phosphatase non-receptor type 1(PTP1B): a validated therapeutic target for type 2 diabetes and obesity.Since PTP1 B was discovered in 1988,tremendous efforts have been made in finding its inhibitor,but so far,no inhibitor has been used for clinical treatment.In this study,molecular dynamics(MD)simulations were performed to study the binding mechanism of active site inhibitor(TCS401)and allosteric inhibitors(benzofuran compounds),and explore the connection between the active site and allosteric site.The results show that there is a hydrogen bond network(THR177-TYR152-ASN193-GLU297)connecting the active site and allosteric site.This hydrogen bond network is an important factor to maintain the WPD loop open or close and act as a signal propagation pathway to transfer the structure changes.ASN193 is the pivotal residue as it could connect key regions loop L11 and helix ?7.In addition,the dual dissociation state of TCS401 has a superior binding affinity to PTP1 B than other states.Our study reveals a potential allosteric regulatory mechanism of PTP1 B,which could give a new insight for the design of new allosteric inhibitors.2.Exploring the allosteric mechanism of Src homology-2 domain-containing protein tyrosine phosphatase 2(SHP2)by molecular dynamics simulationsThe Src homology-2(SH2)domain-containing protein tyrosine phosphatase 2(SHP2,encode by PTPN11)is a critical allosteric enzyme for many signaling pathways.Programmed cell death 1(PD-1)could be phosphorylated at its immunoreceptor tyrosine-based inhibitory motif(ITIM)and immunoreceptor tyrosine-based switch motif(ITSM)and bind to SHP2 to initiate T cell inactivation.Although the interaction of SHP2-PD-1 plays an important role in immune process,the complex structure and the allosteric regulation mechanism remain unknow.In this study,molecular dynamics(MD)simulations were performed to study the binding details of SHP2 and PD-1,and explore the allosteric regulation mechanism of SHP2.The results show that ITIM has a preference to bind the N-SH2 domain and ITSM has almost the same binding affinity to N-SH2 and C-SH2 domain.Only when ITIM binds to N-SH2 domain and ITSM binds to C-SH2 domain can obtain the full activation of SHP2.The binding of ITIM and ITSM could change the motion mode of SHP2 and switch it to the activate state.3.Exploring the distinct binding and activation mechanisms for different CagA oncoproteins and SHP2 by molecular dynamics simulationsCagA is a major virulence factor of Helicobacter pylori.H.pylori CagA is geographically subclassified into East Asian CagA and Western CagA,which are characterized by the presence of EPIYA-D or EPIYA-C segment.The East Asian CagA is more closely associated with gastric cancer than the Western CagA.In this study,molecular dynamic(MD)simulations were performed to investigate the binding details of SHP2 and EPIYA segments,and to explore the allosteric regulation mechanism of SHP2.Our results show that the EPIYA-D has stronger binding affinity to the N-SH2 domain of SHP2 than EPIYA-C.In addition,a single EPIYA-D binding to N-SH2 domain of SHP2 can cause a deflection of the key helix B.And the deflected helix B could squeeze the N-SH2 and PTP domains to break the autoinhibition pocket of SHP2.However,a single EPIYA-C binding to the N-SH2 domain of SHP2 cannot break the autoinhibition of SHP2 because the secondary structure of the key helix B is destroyed.But the tandem EPIYA-C not only increases its binding affinity to SHP2,but also does not significantly break the secondary structure of the key helix B.Our study can help us better understand the mechanism of gastric cancer causing by Helicobacter pylori infection.PTP1B and SHP2 are not only two very representative members of the PTPs superfamily,but also effective targets for the treatment of diabetes and tumors.However,due to the particularity of their catalytic sites,their competitive inhibitors face many difficulties in clinical treatment.In this study,we used molecular dynamics simulation methods to explain the allosteric regulation mechanism of PTP1 B and SHP2,and provided theoretical support for the development of allosteric inhibitors of PTP1 B and SHP2.