The FK506-binding proteins have been targets of pharmaceutical interests over years. We have studied the binding of a set of 12 nonimmunosuppressive small-molecule inhibitors to FKBP12 through molecular dynamics simulations. Each complex was subjected to 1-ns MD simulation conducted in an explicit solvent environment under constant temperature and pressure. The binding free energy of each complex was then computed by the MM-PB/SA method in the AMBER program. Our MM-PB/SA computation produced a good correlation between the experimentally determined and the computed binding free energies with a correlation coefficient (R(2)) of 0.93 and a standard deviation as low as 0.30 kcal/mol. The vibrational entropy term given by the normal mode analysis was found to be helpful for achieving this correlation. Moreover, an adjustment to one weight factor in the PB/SA model was essential to correct the absolute values of the final binding free energies to a reasonable range. A head-to-head comparison of our MM-PB/SA model with a previously reported Linear Response Approximation (LRA) model suggested that the MM-PB/SA method is more robust in binding affinity prediction for this class of compounds.

A computational analysis of the binding affinities of FKBP12 inhibitors using the MM-PB/SA method.

Ectodomain orientation, conformational plasticity and oligomerization of ErbB1 receptors investigated by molecular dynamics

Microsomal prostaglandin E synthase-1 (mPGES-1) is an essential enzyme involved in a variety of diseases and is the most promising target for the design of next-generation anti-inflammatory drugs. In order to establish a solid structural base, we recently developed a model of mPGES-1 trimer structure by using available crystal structures of both microsomal glutathione transferase-1 (MGST1) and ba3-cytochrome c oxidase as templates. The mPGES-1 trimer model has been used, in the present study, to examine the detailed binding of mPGES-1 trimer with substrate PGH2 and cofactor GSH. Results obtained from the computational alanine scanning reveal the contribution of each residue at the protein-ligand interaction interface to the binding affinity, and the computational predictions are supported by the data obtained from the corresponding wet experimental tests. We have also compared our mPGES-1 trimer model with other available 3D models, including an alternative homology model and a low-resolution crystal structure, and found that our mPGES-1 trimer model based on the crystal structures of both MGST1 and ba3-cytochrome c oxidase is more reasonable than the other homology model of mPGES-1 trimer constructed by simply using a low-resolution crystal structure of MGST1 trimer alone as a template. The available low-resolution crystal structure of mPGES-1 trimer represents a closed conformation of the enzyme and, thus, is not suitable for studying mPGES-1 binding with ligands. Our mPGES-1 trimer model represents a reasonable open conformation of the enzyme and is, therefore, promising for studying mPGES-1 binding with ligands in future structure-based drug design targeting mPGES-1.

/pdf/understanding-microscopic-binding-of-human-microsomal-40oakei2uw.pdf

Understanding microscopic binding of human microsomal prostaglandin E synthase-1 (mPGES-1) trimer with substrate PGH2 and cofactor GSH: insights from computational alanine scanning and site-directed mutagenesis.

A thorough investigation of different roles of Escherichia coli type I signal peptidase residues binding to lipopeptide inhibitor has been performed by a combination of computational alanine scanning mutagenesis and free energy decomposition methods. PB and GB models are both used to evaluate the binding free energy in computational alanine scanning method and only GB model can be used to decompose the binding free energy on a per-residue basis. The regression analysis between the PB and GB model and also between the computational alanine scanning and free energy decomposition have been reported with a correlation coefficient of 0.96 and 0.83, respectively, which suggest they are both in fair agreement with each other. Moreover, the contribution components from van der Waals, electrostatic interaction, non-polar and polar energy of solvation, have been determined as well as the effects of backbones and side-chains. The results indicate that Lys145 is the most important residue for the binding but also acts as a general base, activating Ser90 to increase its nucleophility, recognizing and stabilizing the binding of lipopeptide inhibitor to the E. coli SPase. The hydroxyl group of Ser88 plays a key role for the binding of the inhibitor. Ser90 contributes more to the intramolecular interaction than to the intermolecular interaction. Tyr143 and Phe84 contribute larger van der Waals interaction energies, indicating that these residues can be important for the selection based on the shape of the inhibitors. The contributions from other several interfacial residues of the E. coli SPase are also analyzed. This study can be a guide for the optimization of lipopeptide inhibitors and future design of new therapeutic agents for the treatment of bacterial infections.

Computational alanine scanning and free energy decomposition for E. coli type I signal peptidase with lipopeptide inhibitor complex.

Human cellular protein LEDGF/p75 (lens epithelium-derived growth factor) is an important binding partner of human immunodeficiency virus type 1 (HIV-1) integrase (IN). Without LEDGF/p75, HIV-1 can not complete its life cycle. To study the detailed interactions between LEDGF/p75 and HIV-1 IN, and then obtain the hotspots at the binding interface, 13 ns molecular dynamics simulations were carried out here. One-hundred snapshots extracted from the last 4 ns trajectories were used for calculation of binding free energy and decomposition of the energy by residue. First, the structural changes and their dynamic interactions were investigated focused on the production stage. And then, the free energy was discussed. On the basis of the above results, it could be suggested that residues Gln168, Glu170, and Thr174 in chain A of IN, Thr125, and Trp131 in chain B of IN as well as Ile365, Asp366, Phe406, and Val408 in LEDGF/p75 were responsible for their binding. These results might be helpful for discovery and design of small molecules to interrupt the interaction between HIV-1 IN and LEDGF/p75. Proteins 2008. © 2008 Wiley-Liss, Inc.

Insights into the interactions between HIV-1 integrase and human LEDGF/p75 by molecular dynamics simulation and free energy calculation.

The neuregulin/ErbB system is a growth factor/receptor cascade that has been proven to be essential in the development of the heart and the sympathetic nervous system. However, the basis of the specificity of ligand-receptor recognition remains to be elucidated. In this study, the structures of NRG-1beta/ErbB3 and NRG-1beta/ErbB4 complexes were modeled based on the available structures of the homologous proteins. The binding free energies of NRG-1beta to ErbB3 and ErbB4 were calculated using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) computational method. In addition, computational alanine-scanning mutagenesis was performed in the binding site of NRG-1beta and the difference in the binding free energies between NRG-1beta mutants and the receptors was calculated. The results specify the contribution of each residue at the interaction interfaces to the binding affinity of NRG-1beta with ErbB3 and ErbB4, identifying several important interaction residue pairs that are in agreement with previously acquired experimental data. This indicates that the presented structural models of NRG-1beta/ErbB3 and NRG-1beta/ErbB4 complexes are reliable and could be used to guide future studies, such as performing desirable mutations on NRG-1beta to increase the binding affinity and selectivity to the receptor and discovering new therapeutic agents for the treatment of heart failure.

Computational analysis of molecular basis of 1:1 interactions of NRG-1beta wild-type and variants with ErbB3 and ErbB4.


 Background: Examine the association of serum Lp(a) with sarcopenia in Chinese elderly.Methods: We conducted this study using 2015–2020 data from hospitalized Chinese people 60 years old and older. Total body fat percentage and appendicular skeletal muscle mass were assessed with a dual-energy X-ray absorptiometry scan. We classified the participants into four sarcopenia/obesity groups based on both total body fat percentage and appendicular skeletal muscle mass.Results: The analysis included data of 528 participants. the LP(a) level of sarcopenia was significantly higher than no sarcopenia, compared with obese or no obese groups. Furthermore, In the sarcopenic obesity group, the LP(a) level was highest. Correlation analysis showed that ASM/height2 was negatively correlated with LP(a). Logistic regression analysis showed that sarcopenia was positively associated with LP(a).Conclusions: Our study shows that sarcopenia appeared to be significantly associated with Lp(a) no matter the subjects had obesity or not.

/pdf/relationships-between-serum-lipoprotein-a-and-sarcopenia-in-3upp26h7.pdf

Relationships Between Serum Lipoprotein (a) And Sarcopenia In Elderly

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Computational analysis of molecular basis of 1:1 interactions of NRG-1beta wild-type and variants with ErbB3 and ErbB4.

Relationships Between Serum Lipoprotein (a) And Sarcopenia In Elderly