Insights into the functional role of protonation states in the HIV-1 protease-BEA369 complex: molecular dynamics simulations and free energy calculations

Chen, Jianzhong; Yang, Maoyou; Hu, Guodong; Shi, Suhua; Yi, Cao

doi:10.1007/s00894-009-0452-y

Cited by 32 publications

(25 citation statements)

References 28 publications

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“…In contrast, the wild type unprotonated system exhibits an average RMSD value of 1.42 Å with a deviation of 0.15 Å from the mean. Similar results were obtained for the HIV-1 PR-BEA369 complex [14].…”

Section: Structural Stabilitysupporting

confidence: 85%

“…Often it is assumed that the protonation state yielding the highest affinity is the correct one [14]. However, there is no physical reason to assume this.…”

Section: Experimental Protonation State From Pk a Calculationsmentioning

confidence: 99%

“…Endpoint free energy calculations using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method show that the inhibitor BEA369 binds most strongly to HIV-1 PR in the mono25 state [14]. A study using free energy perturbation indicated that the HIV-1 PR in the mono25 state is also the protonation state with the highest affinity for the S and R isomer of the inhibitor U85548E [15].…”

Section: Introductionmentioning

confidence: 99%

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Energetic basis for drug resistance of HIV-1 protease mutants against amprenavir

Kar

Knecht

2012

J Comput Aided Mol Des

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Amprenavir (APV) is a high affinity (0.15 nM) HIV-1 protease (PR) inhibitor. However, the affinities of the drug resistant protease variants V32I, I50V, I54V, I54M, I84V and L90M to amprenavir are decreased 3 to 30-fold compared to the wild-type. In this work, the popular molecular mechanics Poisson-Boltzmann surface area method has been used to investigate the effectiveness of amprenavir against the wild-type and these mutated protease variants. Our results reveal that the protonation state of Asp25/Asp25' strongly affects the dynamics, the overall affinity and the interactions of the inhibitor with individual residues. We emphasize that, in contrast to what is often assumed, the protonation state may not be inferred from the affinities but requires pK(a) calculations. At neutral pH, Asp25 and Asp25' are ionized or protonated, respectively, as suggested from pK(a) calculations. This protonation state was thus mainly considered in our study. Mutation induced changes in binding affinities are in agreement with the experimental findings. The decomposition of the binding free energy reveals the mechanisms underlying binding and drug resistance. Drug resistance arises from an increase in the energetic contribution from the van der Waals interactions between APV and PR (V32I, I50V, and I84V mutant) or a rise in the energetic contribution from the electrostatic interactions between the inhibitor and its target (I54M and I54V mutant). For the V32I mutant, also an increased free energy for the polar solvation contributes to the drug resistance. For the L90M mutant, a rise in the van der Waals energy for APV-PR interactions is compensated by a decrease in the polar solvation free energy such that the net binding affinity remains unchanged. Detailed understanding of the molecular forces governing binding and drug resistance might assist in the design of new inhibitors against HIV-1 PR variants that are resistant against current drugs.

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Section: Structural Stabilitysupporting

confidence: 85%

“…Often it is assumed that the protonation state yielding the highest affinity is the correct one [14]. However, there is no physical reason to assume this.…”

Section: Experimental Protonation State From Pk a Calculationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Energetic basis for drug resistance of HIV-1 protease mutants against amprenavir

Kar

Knecht

2012

J Comput Aided Mol Des

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“…[8] A quite few other studies also dealt with the ligand binding interactions and multi-drug resistance in HIV-1-pr using the method of MM-PBSA. [9-21]…”

Section: Introductionmentioning

confidence: 99%

Exploring the drug resistance of V32I and M46L mutant HIV-1 protease to inhibitor TMC114: Flap dynamics and binding mechanism

Meher

Wang

2015

Journal of Molecular Graphics and Modelling

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Inhibitors of HIV-1 protease (HIV-1-pr) generally only bind to the active site of the protease. However, for some mutants such as V32I and M46L the TMC114 can bind not only to the active cavity also to the groove of the flexible flaps. Although the second binding site suggests the higher efficiency of the drug against HIV-1-pr, the drug resistance in HIV-1-pr due to mutations cannot be ignored, which prompts us to investigate the molecular mechanisms of drug resistance and behavior of double bound TMC114 to HIV-1-pr. The conformational dynamics of HIV-1-pr and the binding of TMC114 to the WT, V32I and M46L mutants were investigated with all-atom molecular dynamic (MD) simulation. The 20 ns MD simulation shows many fascinating effects of the inhibitor binding to the WT and mutant proteases. MM-PBSA calculations explain the binding free energies unfavorable for the M46L and V32I mutants as compared to the WT. For the single binding the less binding affinity can be attributed to the entropic loss for both V32I-1T and M46L-1T. Although the second binding of TMC114 with flap does increase binding energy for the mutants (V32I-2T and M46L-2T), the considerable entropy loss results in the lower binding Gibbs free energies. Thus, binding of TMC114 in the flap region doesn't help much in the total gain in binding affinity of the system, which was verified from this study and thereby validating experiments.

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“…So far as we know, computer-aided approaches and models do not only help experimentalists to explain their observations, but also give them valuable information and suggestions to optimize the drug screening procedure among the candidate compounds. Especially, with fast increasing in the power of computer, computer-aided approaches and models are widely and successfully used in most fields of the biological investigation [61][62][63][64].…”

Section: Computer-aided Investigations Of Chitin-asesmentioning

confidence: 99%

Investigation of Family 18 Chitinases and Inhibitors by Computer-Aided Approaches

Chu

Wang²,

Shen³

et al. 2012

CDT

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Chitinases belong to family 18 glycosyl hydrolases that can hydrolyze chitin by cleaving β-1,4-glycosidic bond, and are at key points in the life cycles of organism. The inhibitors of chitinases not only have chemotherapeutic potential against fungi, insects, but also hold anti-inflammatory efficacy against asthma and allergic disease in human. This review summarizes the structural characters of chitinases, the proposed catalytic mechanism, furthermore, also gives descriptions of currently existing inhibitors. In addition, computational studies of the interaction modes of chitinases with different inhibitors and substrates, as well as the inhibitor design of chitinases, are summarized so as to obtain an overall understanding for chitinases.Keywords: Chitinases, chitinase inhibitors, computer-aided approach. CHITIN AND CHITINASESChitin (C 8 H 13 O 5 N) n (shown in Fig. 1a), a linear insoluble homopolymer of N-acetyl-D-glucosamine (GlcNAc), is the second most abundant polysaccharide on the earth next to the cellulose [1, 2] and has been found in a wide range of organism, including bacteria, fungi, insects, and viruses [3][4][5].Accumulation of chitin in an organism is modulated by chitin synthase-mediated biosynthesis and chitinases-mediated hydrolytic degradation [6]. Since chitin synthases have become an ideal target for the development of pesticides and fugicides in agriculture, the design of chitin synthase's inhibitors has attracted much more attention [7,8]. Recently, some chitin synthase inhibitors have been successfully designed and synthesized in the group of Dr. Qing Yang [6,9], and these synthesized inhibitors were claimed to be novel potential agents due to their bioactivities. Chitinases (EC 3.2.1.14) play a key role in hydrolyzing β-1,4-glycosidic bond of the chitin into low molecular weight, soluble oligomers of GlcNAc [10,11]. Chitinases are currently classified into two different families of glycosyl hydrolases, namely family 18 and family 19 [12][13][14], and this review mainly focuses on family 18 chitinases studies, information available from their three-dimensional structures and the biochemistry of reaction. Chitinases are also widespread, and perform different functions in the different organism [15][16][17][18][19][20]. Although chitin does not exist in mammals, human chitinase family members, such as acidic mammalian chitinase (AMCase), have also been described in previous Therefore, the design of chitinases inhibitors is of great interest. The well-known inhibitor allosamidin (shown in Fig. 1b) is the most potent broad-spectrum inhibitor of chitinases. It inhibits chitinases by mimicing the reaction intermediate [24], but unfortunately, the synthesis of allosamidin and its derivatives are very difficult and expensive, which makes it a less suitable candidate targating a common chemotherapeutical therapy [25]. Izumida et al. found another effective chitinases inhibitor, the cyclic dipeptide [cyclo-(L-Arg-D-pro)] CI-4 (shown in Fig. 1c) [26]. CI-4 shows relatively weak inhibition ...

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Insights into the functional role of protonation states in the HIV-1 protease-BEA369 complex: molecular dynamics simulations and free energy calculations

Cited by 32 publications

References 28 publications

Energetic basis for drug resistance of HIV-1 protease mutants against amprenavir

Energetic basis for drug resistance of HIV-1 protease mutants against amprenavir

Exploring the drug resistance of V32I and M46L mutant HIV-1 protease to inhibitor TMC114: Flap dynamics and binding mechanism

Investigation of Family 18 Chitinases and Inhibitors by Computer-Aided Approaches

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