Yumin Li

Molecular dynamics studies on troponin (TnI-TnT-TnC) complexes: insight into the regulation of muscle contraction.

Abstract Mutations of any subunit of the troponin complex may lead to serious disorders. Rational approaches to managing these disorders require knowledge of the complex interactions among the three subunits that are required for proper function. Molecular dynamics (MD) simulations were performed for both skeletal (sTn) and cardiac (cTn) troponin. The interactions and correlated motions among the three components of the troponin complex were analyzed using both Molecular Mechanics-Generalized Born Surface Area (MMGBSA) and cross-correlation techniques. The TnTH2 helix was strongly positively correlated with the two long helices of TnI. The C domain of TnC was positively correlated with TnI and TnT. The N domain of TnC was negatively correlated with TnI and TnT in cTn, but not in sTn. The two C-domain calcium-binding sites of TnC were dynamically correlated. The two regulatory N-domain calcium-binding sites of TnC were dynamically correlated, even though the calcium-binding site I is dysfunctional. The strong interaction residue pairs and the strong dynamically correlated residues pairs among the three components of troponin complexes were identified. These correlated motions are consistent with the idea that there is a high degree of cooperativity among the components of the regulatory complex in response to Ca2+ and other effectors. This approach may give insight into the mechanism by which mutations of troponin cause disease. It is interesting that some observed disease causing mutations fall within regions of troponin that are strongly correlated or interacted.

Acridinone/amine(carbazole)-based bipolar molecules: efficient hosts for fluorescent and phosphorescent emitters.

Three acridinone-based molecules ADBP, ACBP, and DABP were synthesized, and their application to the OLED devices was investigated. When used as the host for either the deep blue singlet or the green triplet emitter in OLED devices, the bipolar molecules ADBP and ACBP demonstrated superior performance compared to either DABP or commonly used host CBP, remarkably lowering the drive voltage and improving efficiencies.

Molecular Dynamics and Docking Studies on Cardiac Troponin C

Abstract Cardiac troponin C (cTnC) is the Ca2+ dependent switch for contraction in heart muscle making it a potential target for drug research in the therapy of heart failure. Calcium binding on Troponin C (TnC) triggers a series of conformational changes exposing a hydrophobic pocket in the N-domain of TnC (cNTnC), which leads to force generation. Mutations and acidic pH have been related to altering the sensitivity of TnC affecting the efficiency of the heart. Bepridil, identified as a calcium sensitizer to TnC, has been experimentally found to bind to the N-domain pocket of TnC but with negative cooperativity. Screening and de novo design were carried out using LUDI and AUTOLUDI programs in this work to identify and design potential ligands that can bind to the hydrophobic pocket of TnC. Two docking centers and multiple searching radii including 5Å, 5.5Å, 6Å, 6.5Å, 7.0Å and 7.5Å were used in LUDI to screen the ZINC database. Based on the LUDI docking results, 8 molecules were identified from the database with good potential to bind into the binding pocket and they were used as template molecules to generate a series of new molecules by AUTOLUDI design. Out of all the newly-designed molecules, 14 new ligands were recognized to be potential ligands that can bind and fit well into the binding pocket. These molecules can be used as starting molecules to develop TnC ligands. The binding stability and binding affinity of these molecules to the protein was further analyzed by molecular dynamics simulations. The results show that the binding energies, interactions and complex stabilities of 6 ligands are comparable to or better than bepridil.

Molecular dynamics simulation studies on Ca2+-induced conformational changes of annexin I

Cryo-electron microscopy (EM) and X-ray studies proposed different mechanisms for annexin-induced membrane aggregation. In this work, molecular dynamics (MD) simulation technique was utilized to gain an insight into the calcium-induced conformational changes on annexin I and their implication in membrane aggregation mechanism. MD simulations were performed on the Ca2+ -free annexin I with the N-terminal domain buried inside the core (System 1), the Ca2+ -bound annexin I without N-terminal domain (System 2) and the Ca2+ -bound annexin I with the N-terminal domain exposed (System 3). Our results indicated that calcium binding increases the flexibility of annexin I core domain residues including the calcium coordinating residues. As a result, annexin I was activated to interact with the negatively charged membrane. The exposed N-terminal domain was very flexible and gradually lost the secondary structure during MD simulation, suggesting that the N-terminal may adopt a favorable conformation to bind a second membrane and also explaining the failure of attempts to crystallize the full-length annexin I in the presence of calcium ions. The measured dimensions of the averaged simulation structure of the Ca2+ -bound annexin I with the N-terminal exposed (System 3) support the proposed membrane aggregation mechanism based on X-ray studies.

A computational and experimental approach to investigate bepridil binding with cardiac troponin.

Cardiac troponin is a Ca(2+)-dependent switch for the contraction in heart muscle and a potential target for drugs in the therapy of heart failure. Bepridil is a drug that binds to troponin and increases calcium sensitivity of muscle contraction. Because bepridil has been well studied, it is a good model for analysis by computational and experimental methods. Molecular dynamics (MD) simulations were performed on troponin complexes of different sizes in the presence and absence of bepridil bound within the hydrophobic pocket at the N-terminal domain of troponin C. About 100 ns of simulation trajectory data were generated, which were analyzed using cross-correlation analyses and MMPBSA and MMGBSA techniques. The results indicated that bepridil binding within the hydrophobic pocket of cardiac TnC decreases the interaction of TnC with TnI at both the N-domain of TnC and the C-domain of TnC, and decreases the correlations of motions among the segments of the troponin subunits. The estimated calcium-binding affinities using MMPBSA showed that bepridil has a sensitizing effect for the isolated system of TnC, but loses this effect for the complex. Our experimental measurements of calcium dissociation rates were consistent with that prediction. We also observed that while bepridil enhanced the troponin-tropomyosin-actin-activated ATPase activity of myosin S1 at low calcium concentrations it was slightly inhibitory at high calcium concentrations. Bepridil increases the ATPase activity and force generation in muscle fibers, but its effects appear to depend on the concentration of calcium.

Computational screening and design of S100B ligand to block S100B-p53 interaction.

The binding of S100B to p53 disables the biological function of p53 as a tumor suppressor and thus causes cancer. It is very important to explore the interaction between S100B and p53 and to develop inhibitors to block the interaction in anti-cancer development. In this work, the interaction of S100B to p53 was studied using molecular dynamics (MD) at the atomic level and organic molecules have been identified as potential inhibitors to block the S100B-p53 interaction. It was indicated in the simulations that S100B residues around GLU45 and GLU46 play an important role in the binding of S100B to p53. The three dimensional structure of S100B obtained from S100B-p53 complex (PDB ID: 1DT7) was used as the target protein receptor. Multiple LUDI screenings for S100B ligands were performed using different searching radii 6.23 A, 7.23 A, 8.23 A, 9.23 A and 10.23A with a searching center which was defined as the geometrical center of S100B residues that are within 5A from the p53 C-terminal peptide in the complex. Potential organic compounds were screened from the ZINC database using LUDI program implemented in Cerius2 package and evaluated as potential S100B ligands to block the S100B-p53 interaction. The top-scored compounds were selected for binding affinity calculation. The results show that these top-scored ZINC compounds bind in the location where p53 binds and interact with S100B in a similar fashion as p53, and therefore it is expected that they have the potential to block S100B from binding to p53. The ADME and toxicity properties of the potential S100B ligands were also evaluated.

Multireference configuration interaction studies on the ground and excited states of N2O2: the potential energy curves of N2O2 along N-N distance.

In this paper, the ground and excited states of N2O2 were studied at the multireference configuration interaction (MRCI) level of theory with Dunnings [J. Chem. Phys. 90, 1007 (1985); 96, 6796 (1992)] correlation consistent basis sets augo-cc-pVDZ and aug-cc-pVTZ. The geometry optimizations were performed for the ground state of N2O2. The vertical excitation energies and transition moments were calculated for the low-lying singlet states of N2O2 including the lowest three 1A1 states, two 1B1 states, one 1B2 state, and two 1A2 states at the MRCI level of theory with Dunnings correlation consistent basis sets aug-cc-pVDZ, aug-cc-pVTZ, and aug-cc-pVQZ. Furthermore, for the first time, the potential energy curves were calculated at the complete active space self-consistent-field and MRCI levels of theory for as many as 12 N2O2 singlet electronic states along the N-N distance. The dissociation asymptotes of these 12 N2O2 singlet electronic states were discussed.

The N-terminal of annexin A1 as a secondary membrane binding site: A molecular dynamics study

Annexin A1 has been shown to cause membrane aggregation and fusion, yet the mechanism of these activities is not clearly understood. In this work, molecular dynamics simulations were performed on monomeric annexin A1 positioned between two negatively charged monolayers using AMBERs all atom force field to gain insight into the mechanism of fusion. Each phospolipid monolayer was made up of 180 DOPC molecules and 45 DOPG molecules to achieve a 4:1 ratio. The space between the two monolayers was explicitly solvated using TIP3P waters in a rectilinear box. The constructed setup contained up to 0.14 million atoms. Application of periodic boundary conditions to the simulation setup gave the desired effect of two continuous membrane bilayers. Nonbonded interactions were calculated between the N‐terminal residues and the bottom layer of phospholipids, which displayed a strong attraction of K26 and K29 to the lipid head‐groups. The side‐chains of these two residues were observed to orient themselves in close proximity (∼3.5 Å) with the polar head‐groups of the phospholipids. Proteins 2014; 82:2936–2942.

Multiconfigurational self-consistent field and multireference internally contracted configuration interaction studies on the excited states of weakly bonded NO2 dimer (N2O4)

In this paper, the vertical excitation energies of total of 32 states of N(2)O(4) including the lowest two singlet states and two triplet states of each of the A(g), B(3u), B(2u), B(1g), B(1u), B(2g), B(3g), and A(u) symmetries were calculated at multiconfigurational self-consistent field (MCSCF) and the multireference internally contracted configuration interaction (MRCI) levels of theory on the active space (15o,16e) with aug-cc-pVDZ basis set. The potential energy curves of the eight singlet states(1 (1)A(g), 1 (1)B(3u), 1 (1)B(2u), 1 (1)B(1g), 1 (1)B(1u), 1 (1)B(2g), 1 (1)B(3g), and 1 (1)A(u)) and eight triplet states (1 (3)A(g), 1 (3)B(3u), 1 (3)B(2u), 1 (3)B(1g), 1 (3)B(1u), 1 (3)B(2g), 1 (3)B(3g), and 1 (3)A(u)) were calculated at MCSCF and MRCI levels of theory on the active space (15o,16e) with aug-cc-pVDZ basis set along the N-N distance. The vertical excitation energies of 1 (1)B(3u), 1 (1)B(2u), and 1 (1)B(1u) states with nonzero transition moment are 4.60 eV (269.6 nm), 6.06 eV (204.6 nm), and 7.71 eV (160.8 nm), respectively, at MRCI level of theory. The photodissociation asymptotics were assigned as NO(2)(X (2)A(1))+NO(2)(X (2)A(1)) for ground state 1 (1)A(g) and the 1 (3)B(1u) state, NO(2)(X (2)A(1))+NO(2)(1 (2)A(2)) for the 1 (1)B(1g), 1 (3)B(1g), 1 (1)A(u), and 1 (3)A(u) states, NO(2)(X (2)A(1))+NO(2)(1 (2)B(1)) for the 1 (1)B(3u), 1 (3)B(3u), 1 (1)B(2g), and 1 (3)B(2g) states, and NO(2)(X (2)A(1))+NO(2)(1 (2)B(2)) for the 1 (1)B(2u), 1 (3)B(2u), 1 (1)B(3g), and 1 (3)B(3g) states.

Computational studies on the ground and excited states of BrOOBr.

In this work, theoretical computations for the ground and excited states of BrOOBr have been performed at high-level ab initio molecular orbital theories. The ground-state geometries of BrOOBr in different forms (trans, cis, and twist form) have been optimized at the couple-cluster CCSD(T) level of theory with cc-pVTZ and aug-cc-pVTZ basis sets, which indicates that at CCSD(T)/cc-pVTZ level of theory, the twist form is 4.96 kcal/mol more stable than the trans form and 10.67 kcal/mol more stable than the cis form; at the CCSD(T)/aug-cc-pVTZ basis set the twist form is 4.33 kcal/mol more stable than the trans form and 9.54 kcal/mol more stable than the cis form. The vertical excitation energies and potential-energy curves for the singlet and triplet low-lying excited states of BrOOBr were calculated at both the complete active space self-consistent-field (CASSCF) level of theory and the multireference internally contracted configuration interaction (MRCI) level of theory. The differences of potential-energy curves at CASSCF and MRCI levels of theory are found for the BrOOBr excited states. At CASSCF level of theory, none of the BrOOBr excited states are bound. However, at MRCI level of theory, all the BrOOBr states studied in this work are bound or slightly bound at the Frank-Condon region. In addition, the scalar relativistic effect and the spin-orbital coupling effect on the vertical excitation energies of the electronic states of BrOOBr were estimated.