Pair Interaction Energy Decomposition Analysis Research Articles

The Pivotal Distinction between Antagonists' and Agonists' Binding into Dopamine D4 Receptor-MD and FMO/PIEDA Studies.

The dopamine D4 receptor (D4R) is a promising therapeutic target in widespread diseases, and the search for novel agonists and antagonists appears to be clinically relevant. The mechanism of binding to the receptor (R) for antagonists and agonists varies. In the present study, we conducted an in-depth computational study, teasing out key similarities and differences in binding modes, complex dynamics, and binding energies for D4R agonists and antagonists. The dynamic network method was applied to investigate the communication paths between the ligand (L) and G-protein binding site (GBS) of human D4R. Finally, the fragment molecular orbitals with pair interaction energy decomposition analysis (FMO/PIEDA) scheme was used to estimate the binding energies of L-R complexes. We found that a strong salt bridge with D3.32 initiates the inhibition of the dopamine D4 receptor. This interaction also occurs in the binding of agonists, but the change in the receptor conformation to the active state starts with interaction with cysteine C3.36. Such a mechanism may arise in the case of agonists unable to form a hydrogen bond with the serine S5.46, considered, so far, to be crucial in the activation of GPCRs. The energy calculations using the FMO/PIEDA method indicate that antagonists show higher residue occupancy of the receptor binding site than agonists, suggesting they could form relatively more stable complexes. Additionally, antagonists were characterized by repulsive interactions with S5.46 distinguishing them from agonists.

Asymmetric Cross Couplings of Trifluoromethyl Radical to Vinylarenes with N‐Hydroxy‐oxazinediones and Subsequent Aerobic Oxidative Homocoupling of 2‐Naphthols Catalysed by Chiral Vanadyl Complexes

AbstractAsymmetric three‐component, 1,2‐aminoxy‐trifluoromethylation of styrenes with N‐hydroxy‐1,3‐benz/naphthoxazine‐2,4‐diones (i. e., N‐OH‐(B/Np)OxzOn) catalysed by chiral vanadyl complexes derived from N‐salicylidene‐L‐t‐leucinate were explored. Among 14 different solvents and 13 different catalysts screened, the best reaction scenarios were in 2‐propanol with 3‐(2,5‐dimethyl)phenyl‐5‐bromo (DMP), or 3‐t‐butyl‐5‐bromo substituted catalysts that led to the corresponding complementary (R)‐ and (S)‐products with potential biological activities in 45–91% yields and up to 85 and 75% ee, respectively. Further optimisation with the DMP catalyst led to the best combination of 3‐halo/3,5‐dihalo‐styrenes with 6‐/7‐Br−N−OH‐(B/Np)OxzOn as the trapping agents. The corresponding eight different products were isolated in 52–75% yields with ees in a range of 88–93% (R). Based on Density Functional Theory (DFT) calculations with conformational searches, the origin of enantiocontrol and the working mechanism were proposed by resorting to a bidentate‐chelation between the amide or carbamate C=O group and N−OH group in the trapping agent to the vanadyl center followed by asymmetric benzylic radical trapping in an SH2 fashion. Subsequent Fragment Molecular Orbital (FMO)/Pair Interaction Energy Decomposition Analysis (PIEDA) calculations with the DMP catalyst were carried out to rationalize the extent of asymmetric induction. One representative product derived from p‐methyl‐styrene and NpOxzOn was hydrolyzed in basic MeOH with decarboxylation to unmask its carbamate moiety. The resulting chiral (R)‐N‐benzoxy‐3‐hydroxy‐2‐naphthamide was subjected to aerobic, oxidative homo‐coupling catalysed by the DMP catalyst in CCl4. The corresponding 2,2‐binaphthol product was isolated in 90% (brsm) yield with nearly complete diastereo‐control at the created (M)‐axial chirality, allowing for sequential, bi‐functional asymmetric cross‐coupling applications.

Comparative study of interaction energies between αIIbβ3 integrin and the peptidic, peptidomimetic and non-peptidic ligands by quantum mechanics FMO-PIEDA calculations

Integrins belong to a family of cell adhesion receptors. To better understand an adhesion mechanism of integrins, fragmented molecular orbital (FMO) method with pair interaction energy decomposition analysis (PIEDA) was applied for integrin:ligand complexes. Interaction energies were evaluated between the amino acid residues including Mg2+ and Ca2+ ions at ligand-binding site of αIIbβ3 integrin and two peptide chains with the Ala-Gly-Asp (AGD)- and the Arg-Gly-Asp (RGD)-binding motifs, a cyclic peptide (eptifibatide), peptidomimetic ligands (tirofiban and L-739758) and poly(l-lactic acid) chain (PLA). The results indicate that Mg2+ and Ca2+ ions together with Asp224A, Asn215B, Asp159A and Lys125B of αIIbβ3 are the most important residues for a binding of the peptidic ligands while for the peptidomimetic ligands and PLA, interactions with Ca2+ ions are less significant than those with amino acid residues of αIIbβ3. For all complexes, a dominant part of interaction energy comes from electrostatic interactions. New developed antagonists of αIIbβ3 should mimic not only the interactions of the RGD motif but also the interactions of the backbone of a longer peptidic sequence (RGDV or AGDV) with the focus on the interactions of the antagonists with the ADMIDAS Ca2+ ion. An interaction pattern predicted for PLA was compared with the native peptidic ligands.

The FMO2 analysis of the ligand-receptor binding energy: the Biscarbene-Gold(I)/DNA G-Quadruplex case study.

In this work, the ab initio fragment molecular orbital (FMO) method was applied to calculate and analyze the binding energy of two biscarbene-Au(I) derivatives, [Au(9-methylcaffein-8-ylidene)2]+ and [Au(1,3-dimethylbenzimidazol-2-ylidene)2]+, to the DNA G-Quadruplex structure. The FMO2 binding energy considers the ligand-receptor complex as well as the isolated forms of energy-minimum state of ligand and receptor, providing a better description of ligand-receptor affinity compared with simple pair interaction energies (PIE). Our results highlight important features of the binding process of biscarbene-Au(I) derivatives to DNA G-Quadruplex, indicating that the total deformation-polarization energy and desolvation penalty of the ligands are the main terms destabilizing the binding. The pair interaction energy decomposition analysis (PIEDA) between ligand and nucleobases suggest that the main interaction terms are electrostatic and charge-transfer energies supporting the hypothesis that Au(I) ion can be involved in π-cation interactions further stabilizing the ligand-receptor complex. Moreover, the presence of polar groups on the carbene ring, as C = O, can improve the charge-transfer interaction with K+ ion. These findings can be employed to design new powerful biscarbene-Au(I) DNA-G quadruplex binders as promising anticancer drugs. The procedure described in this work can be applied to investigate any ligand-receptor system and is particularly useful when the binding process is strongly characterized by polarization, charge-transfer and dispersion interactions, properly evaluated by ab initio methods.

Investigation on the morphology and the permeability of biomimetic cellulose triacetate (CTA) impregnated membranes (IM): In-situ synchrotron imaging, experimental and computational studies

The goal of the present study is to ascertain the controlled permeability of the biomimetic cellulose triacetate (CTA) membranes at different temperatures and salt concentrations by investigating the electrical oscillatory behaviour across the impregnated membranes (IM). The novel biomimetic CTA membranes were infused with a capric fatty acid to induce the electrical oscillatory behavior, and hence, to ensure the controlled permeability. In-situ synchrotron-based X-ray tomography (SR-μCT) at BioMedical Imaging and Therapy (BMIT) Beamline at the Canadian Light Source (CLS) was used to evaluate the main impregnated membrane morphology compared to neat CTA to ensure the fatty acid penetration inside membrane pores along membrane matrices. This study has revealed changes in phase transition temperatures of the impregnated CTA membrane at the melting temperature of the fatty acid. The pulsations of measured voltages were observed to be related to changes in the KCl concentration in the vicinity of the Ag/AgCl electrode. In this study, amplitudes and frequencies of voltage pulsations were dependent on the temperature and concentration of the KCl solution to control the permeability of the biomimetic membrane membranes. Increasing the KCl concentration led to a higher frequency of oscillation which reflects a higher permeability. In addition, no mechanical stirring or disturbance of the system was required for the electrical oscillatory phenomenon to occur. Nevertheless, for the average waveforms, the peak-to-peak value obtained was doubled when stirring was performed, while for the higher amplitude waveforms, the amplitude increased by 5 times. In addition, interactions at the molecular level between water molecules and the fragments of infused membranes at different temperatures and their effect on controlling permeability was investigated using pair interaction energy decomposition analysis (PIEDA) as part of the fragment molecular orbital (FMO) method's framework. Those results opened new frontiers for facilitation and regulation of active transport and permeability through biomimetic smart membranes for a variety of biomedical and drug delivery applications.

Protein-ligand binding affinity prediction of cyclin-dependent kinase-2 inhibitors by dynamically averaged fragment molecular orbital-based interaction energy.

Fragment molecular orbital (FMO) method is a powerful computational tool for structure-based drug design, in which protein-ligand interactions can be described by the inter-fragment interaction energy (IFIE) and its pair interaction energy decomposition analysis (PIEDA). Here, we introduced a dynamically averaged (DA) FMO-based approach in which molecular dynamics simulations were used to generate multiple protein-ligand complex structures for FMO calculations. To assess this approach, we examined the correlation between the experimental binding free energies and DA-IFIEs of six CDK2 inhibitors whose net charges are zero. The correlation between the experimental binding free energies and snapshot IFIEs for X-ray crystal structures was R2 =0.75. Using the DA-IFIEs, the correlation significantly improved to 0.99. When an additional CDK2 inhibitor with net charge of -1 was added, the DA FMO-based scheme with the dispersion energies still achieved R2 =0.99, whereas R2 decreased to 0.32 employing all the energy terms of PIEDA.

Energy Decomposition Analysis of the Adhesive Interaction between an Epoxy Resin Layer and a Silica Surface.

We investigate the adhesive interaction energy (ΔEint) between an epoxy resin and a silica surface using pair interaction energy decomposition analysis (PIEDA), which decomposes ΔEint into four components: electrostatic (ΔEes), exchange repulsion (ΔEex), charge-transfer (ΔEct), and dispersion (ΔEdisp) energies based on quantum chemistry. Our previous study with PIEDA showed that synergistic effects of ΔEes and ΔEdisp are critical at the interface between an epoxy resin fragment and a hydrophilic surface. The present study is designed to show in detail that the synergistic effects are significant at the interface between an epoxy layer model consisting of 20 epoxy monomers and a hydrophilic silica surface. The ratio of the dispersion energies to the total interaction energies of the layer model shows good agreement with experimental values, that is, the dispersion ratio of the work of adhesion (Wad). The 20 epoxy molecules in the layer model are investigated individually to closely correlate the four decomposed energies with their structural features. Our energy-decomposition analyses show that H-bonding and OH-π interactions play important roles at the interface between an epoxy resin and a silica surface. PIEDA calculations for the epoxy layer model also show that the region 3.6 Å from the silica surface accounts for more than 99% of the total interaction energies.

Evaluation of Selective COX-2 Inhibition and In Silico Study of Kuwanon Derivatives Isolated from Morus alba.

Six kuwanon derivatives (A/B/C/E/H/J) extracted from the roots of Morus alba L. were evaluated to determine their cyclooxygenase (COX)-1 and 2 inhibitory effects. Cyclooxygenase (COX) is known as the target enzyme of nonsteroidal anti-inflammatory drugs (NSAIDs), which are the most widely used therapeutic agents for pain and inflammation. Among six kuwanon derivatives, kuwanon A showed selective COX-2 inhibitory activity, almost equivalent to that of celecoxib, a known COX inhibitor. Kuwanon A showed high COX-2 inhibitory activity (IC50 = 14 μM) and a selectivity index (SI) range of >7.1, comparable to celecoxib (SI > 6.3). To understand the mechanisms underlying this effect, we performed docking simulations, fragment molecular orbital (FMO) calculations, and pair interaction energy decomposition analysis (PIEDA) at the quantum-mechanical level. As a result, kuwanon A had the strongest interaction with Arg120 and Tyr355 at the gate of the COX active site (−7.044 kcal/mol) and with Val89 in the membrane-binding domain (−6.599 kcal/mol). In addition, kuwanon A closely bound to Val89, His90, and Ser119, which are residues at the entrance and exit routes of the COX active site (4.329 Å). FMO calculations and PIEDA well supported the COX-2 selective inhibitory action of kuwanon A. It showed that the simulation and modeling results and experimental evidence were consistent.

FMODB: The World's First Database of Quantum Mechanical Calculations for Biomacromolecules Based on the Fragment Molecular Orbital Method.

We developed the world's first web-based public database for the storage, management, and sharing of fragment molecular orbital (FMO) calculation data sets describing the complex interactions between biomacromolecules, named FMO Database (https://drugdesign.riken.jp/FMODB/). Each entry in the database contains relevant background information on how the data was compiled as well as the total energy of each molecular system and interfragment interaction energy (IFIE) and pair interaction energy decomposition analysis (PIEDA) values. Currently, the database contains more than 13 600 FMO calculation data sets, and a comprehensive search function implemented at the front-end. The procedure for selecting target proteins, preprocessing the experimental structures, construction of the database, and details of the database front-end were described. Then, we demonstrated a use of the FMODB by comparing IFIE value distributions of hydrogen bond, ion-pair, and XH/π interactions obtained by FMO method to those by molecular mechanics approach. From the comparison, the statistical analysis of the data provided standard reference values for the three types of interactions that will be useful for determining whether each interaction in a given system is relatively strong or weak compared to the interactions contained within the data in the FMODB. In the final part, we demonstrate the use of the database to examine the contribution of halogen atoms to the binding affinity between human cathepsin L and its inhibitors. We found that the electrostatic term derived by PIEDA greatly correlated with the binding affinities of the halogen containing cathepsin L inhibitors, indicating the importance of QM calculation for quantitative analysis of halogen interactions. Thus, the FMO calculation data in FMODB will be useful for conducting statistical analyses to drug discovery, for conducting molecular recognition studies in structural biology, and for other studies involving quantum mechanics-based interactions.

A comprehensive computational study and simulation of innovative zwitterionic materials for enhanced poly (vinylidene fluoride) membrane hydrophilicity

The goal of this study is to design a novel zwitterionic (ZW)-poly (vinylidene fluoride) (PVDF) membrane with high hydrophilicity potential using the pair interaction energy decomposition analysis (PIEDA) integrated with fragment molecular orbital (FMO) method. In addition, the differential hydration and efficiency of salt rejection of the novel zwitterion and original PVDF were investigated using molecular dynamics simulation (MDS). Within this study computational methods were applied to investigate the performance of zwitterionic moieties derived from three different anionic groups in the ZW head, specifically, carboxylate, sulfonate, and phosphate. This approach was used in addition to the inclusion of a linker between the ZW head and the PVDF backbone, such as trimethyl ammonium groups and hydroxyl group for an increase in PVDF membrane hydrophilicity. The quantum chemical calculations were employed to examine the hydration structure of moieties, the number of hydrogen bonding instances, and hydration free energy. The interactions between the ZW moieties on PVDF membranes with water molecules confirmed that they depended on the charged groups and the chemical groups between charged groups. The results pointed to differences in hydrophilicity, membrane water uptake due to their structural properties depending on the types of anionic groups involved, polar groups between charged groups, and the hydrophilic groups as a linker between charged groups of the zwitterions to the PVDF polymer backbone. The double zwitterionic PMAL®-C8-CB–OH–SB-PVDF was formed through protonated carboxyl group on backbone of copolymer PMAL®-C8, and protonated nitrogen atom of amide group. This double zwitterion showed strong electrostatic interactions between individual water and secondary ammonium and Oxygen of carboxybetaine, compared to PMAL®-C8-OH-SB-PVDF model. The simulated results using MDS confirmed the hydrophilicity of PMAL®-C8-CB–OH–SB-PVDF and showed that the positive and negative centers of zwitterionic polymer chains on PVDF membrane surface can interact with the ions, contributing into the increase of charge density. Our designed hydrophilic zwitterion PVDF membrane, and especially the double zwitterion membrane, is an exciting development that can be used in a broad range of water applications.

Structural Basis of Activin Receptor-Like Kinase 2 (R206H) Inhibition by Bis-heteroaryl Pyrazole-Based Inhibitors for the Treatment of Fibrodysplasia Ossificans Progressiva Identified by the Integration of Ligand-Based and Structure-Based Drug Design Approaches

Fibrodysplasia ossificans progressiva (FOP) is a rare but severe genetic disorder in which acute inflammation elicits progressive heterotopic ossification in the muscles, tendons, and ligaments. Classic FOP is caused by the R206H mutation in ALK2/ACVR1. While several activin receptor-like kinase 2 (ALK2) inhibitors were found to be efficacious in animal models of FOP, most of the ALK2 (R206H) inhibitors lacked sufficient oral bioavailability for efficacy. Previously, the synthesis of a series of novel bis-heteroaryl pyrazole-based ALK2 (R206H) inhibitors that achieved both substantial potency and an improved ADMET profile was reported. In the present study, the detailed procedure of the in silico approach employed to identify the initial bis-heteroaryl pyrazole-based ALK2 (R206H) inhibitor RK-59638 and the analysis of the ALK2 (R206H) RK-59638 complex structure to guide the synthetic optimization of the chemical series, obtaining RK-71807 showing improved potency and metabolic stability, were described. According to the initial in silico screening, the screening efficiencies and chemical diversity of the hit compounds of both ligand-based and structure-based methods were evaluated. Then, X-ray structures of ALK2 (R206H) and the inhibitors were analyzed to assess the structure–activity relationships of the synthesized compounds. The 3D-RISM analysis indicated the existence of the additional hydrogen bond via water molecules restricting the attachment point in the pyrazole scaffold. The quantum mechanics calculation of the newly determined ALK2 (R206H) RK-71807 complex structure using a fragment molecular orbital method and pair interaction energy decomposition analysis was employed to evaluate the interaction energies between the inhibitor and each of the amino acid residues and decompose them to electrostatic, exchange-repulsion, and charge transfer energies. The pattern of decomposed interaction energies was then compared to that formed by RK-59638 and LDN-193189 to investigate the structural basis of ALK2 (R206H) inhibition.

Protein ligand interaction analysis against new CaMKK2 inhibitors by use of X-ray crystallography and the fragment molecular orbital (FMO) method

CaMKK2 (calcium/calmodulin dependent protein kinase kinase 2) is a serine/threonine protein kinase that regulates phosphorylation of CaM kinases (CaMKs) such as CaMKI, CaMKIV, and AMP-activated protein kinase (AMPK). From a pathological perspective, CaMKK2 plays a role in obesity, diabetes, and prostate cancer. Therefore, CaMKK2 is an attractive target protein for drug design. Here, we tried to find new CaMKK2 inhibitors by using ligand-based and structure-based drug design approaches. From the in silico hit compounds, we identified new inhibitors by using a CaMKK2 kinase assay. We solved X-ray crystallography structures of the CaMKK2–inhibitor complexes and performed Fragment Molecular Orbital (FMO) calculations to analyze the protein–ligand interactions, identify the key residues in inhibitor binding, and quantitatively measure their contribution. We experimentally determined five CaMKK2–inhibitor structures and calculated the binding energies of the inhibitors by the FMO method plus MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) approach. The results showed a high correlation (R = −0.89) between experimentally measured inhibitory activity (pIC50) and the predicted ligand binding energy. We then quantitatively evaluated the contribution of each binding site residue in CaMKK2 by the IFIE (Inter-fragment Interaction Energy)/PIEDA (Pair Interaction Energy Decomposition Analysis) method. The IFIE values indicated that Lys194 and Glu236, which formed hydrogen bonds with the carboxylate groups of the inhibitors, were key residues for ligand binding. PIEDA revealed that the dispersion interaction of inhibitors with hydrophobic residues, such as Ile171, Phe267, and Leu319, contributed highly to ligand binding; we considered that this was due to CH-π interactions with methoxy groups and/or aromatic rings contained in our CaMKK2 inhibitor. These results from the quantitative interaction analysis by the FMO method are useful not only for future CaMMK2 inhibitor development but for application of the FMO method to in silico drug design.

Pair interaction energy decomposition analysis (PIEDA) and experimental approaches for investigating water interactions with hydrophilic and hydrophobic membranes

The origins of low and high interactions of polar groups with water molecules are still unknown and need to be further examined for effective future membrane synthesis and modification. The primary aim of this research study is to provide a comprehensive overview of the interactions at the molecular level occurring between water molecules and the fragments of hydrophobic and hydrophilic membranes based on pair interaction energy decomposition analysis (PIEDA) as part of the fragment molecular orbital (FMO) method’s framework. This direction is critical, since a research study of the reasons for water and membrane interactions can help design groundbreaking membranes with superior hydrophilicity characteristics. To accomplish this, the computational studies, the Polyvinylidene fluoride (PVDF [H(–CH2–CF2–)4CH3]) and Polyacrylonitrile (PAN [(H(–CH2–CH(CN)–)4CH3]) membranes were considered as models for hydrophobic and hydrophilic membranes, respectively. Density-functional theory (DFT), based on B3LYP functional and split-valance 6-311+G (d,p) basis sets, was used in order to optimize the geometry of PAN, PVDF, and their complexes with different numbers of water molecules. Furthermore, fragment molecular orbit (FMO) and the Pair Interaction Energy Decomposition Analysis (PIEDA) were carefully interrogated. These types of analyses included the inter fragment interaction energy (IFIE), like the electrostatic (ES), exchange repulsion (EX), charge-transfer and mixing term (CT + mix) energies. Furthermore, the hydrophilicity and hydrophobicity of the origins of membrane function groups were experimentally evaluated through Fourier-transform infrared spectroscopy (FTIR- ATR), 13C cross polarization magic angle spinning (13C CP MAS) Solid State Nuclear magnetic resonance SSNMR, and Fourier transform Raman (FT-Raman) spectroscopies. Confocal microscopic approach was used to interrogate water transport and the interactions between fluorescence particles and membrane layers. Furthermore, the Infrared (IR) spectroscopy was performed to investigate interaction between water molecules and PVDF and PAN. The theoretical results had a good agreement with experimental result.

Analyzing Interactions with the Fragment Molecular Orbital Method.

Basic concepts in the analysis of binding using the fragment molecular orbital method are discussed at length: polarization, desolvation, and interaction. The components in the pair interaction energy decomposition analysis are introduced, and the analysis is illustrated for a water dimer and a protein-ligand complex.

Fully Quantum Chemical Treatment of Chromophore-Protein Interactions in Phytochromes.

The intriguing ability of phytochromes to photoconvert between red-absorbing (Pr) and far-red-absorbing (Pfr) states depends on key interactions between a bilin chromophore and protein matrix. However, both the identification of the chemical nature and quantification of chromophore-protein interactions have not been yet fully investigated by experiments or extensive computations. Here, we presented a powerful and straightforward approach based on the fragment molecular orbital method to identify the nature and quantify the strength of the noncovalent interactions at a fully quantum mechanical level between the biliverdin (BV) chromophore and protein matrix of the Deinococcus radiodurans phytochrome (DrBphP) in the Pr state. By using pair interaction energy decomposition analysis approach, the pyrrole water, Asp207, and Glu27 were detected as key residues for the stabilization of the pyrrole rings of the BV chromophore through the formation of six H-bonds. Furthermore, the conserved Arg254 and His260 were also identified as essential residues in the conformational stability of both propionic side chains B and C. Moreover, new interactions were identified in the chromophore-binding pocket, two nonclassical H-bonds (CH/O interactions) between Asp207 and Tyr263, and an OH/π interaction between Tyr263 and ring D of the BV chromophore, which might have photochemical relevance.

Current Status of ABINIT-MP Open Series

We have been developing an original program named ABINIT-MP for fragment molecular orbital (FMO) calculations. Various functionalities for interaction analyses, e.g. PIEDA (Pair Interaction Energy Decomposition Analysis), have been augmented in Revision 10 and Revision 15 of the ABINIT-MP Open Series Version 1. In this Letter, we briefly describe such new features.

Investigation of Hot Spot Region in XIAP Inhibitor Binding Site by Fragment Molecular Orbital Method

X-linked inhibitor of apoptosis protein (XIAP) is an important regulator of cancer cell survival whose BIR3 domain (XIAP-BIR3) recognizes the Smac N-terminal tetrapeptide sequence (AVPI), making it an attractive protein-protein interaction (PPI) target for cancer therapies. We used the fragment molecular orbital (FMO) method to study the binding modes and affinities between XIAP-BIR3 and a series of its inhibitors (1–8) that mimic the AVPI binding motif; the inhibitors had common interactions with key residues in a hot spot region of XIAP-BIR3 (P1–P4 subpockets) with increased binding affinity mainly attributed to specific interactions with the P1 and P4 subpockets. Based on the structural information from FMO results, we proposed a novel XIAP natural product inhibitor, neoeriocitrin 10, which was derived from our preciously reported XIAP-BIR3 inhibitor 9, can be used as a highly potent candidate for XIAP-BIR3 inhibition. We also performed pair interaction energy decomposition analysis to investigate the binding energies between specific binding residues and individual ligands, showing that the novel natural product neoeriocitrin 10 had a higher binding affinity than epicatechin gallate 9. Molecular docking and dynamics simulations were performed to explore the mode of binding between 10 and XIAP-BIR3, demonstrating that 10 binds more strongly to the P1 and P4 pockets than 9. Overall, we present a novel natural product, neoeriocitrin 10, and demonstrate that the FMO method can be used to identify hot spots in PPIs and design new compounds for XIAP inhibition.

Interaction between a Single-Stranded DNA and a Binding Protein Viewed by the Fragment Molecular Orbital Method

Abstract The interaction between a single-stranded DNA (ssDNA) and a binding protein (Sulfolobus solfataricus ssDNA binding protein, SSB) were investigated by the ab initio fragment molecular orbital (FMO) method in explicit solvent. The calculated overall energy change upon complexation suggested that the ssDNA/SSB association is not strong. Nonetheless, more detailed analysis of interfragment interaction energy (IFIE) and pair interaction energy decomposition analysis (PIEDA) indicated that the ssDNA/SSB association is based upon a minute balance of various contributions of local structural parts of the molecules. The most stabilizing contribution was that by the electrostatic interaction between the sugar–phosphate backbone of ssDNA and charged side chains of SSB, and the second was that by the stacking interaction between bases of ssDNA and aromatic side chains of SSB. Thus, though the overall association energy change was small, the local interactions were suggested to contribute to the association.

Empirical corrections and pair interaction energies in the fragment molecular orbital method

The energy and analytic gradient are developed for FMO combined with the Hartree-Fock method augmented with three empirical corrections (HF-3c). The auxiliary basis set approach to FMO is extended to perform pair interaction energy decomposition analysis. The FMO accuracy is evaluated for several typical systems including 3 proteins. Pair interaction energies computed with different approaches in FMO are compared for a water cluster and protein-ligand complexes.

Pair Interaction Energy Decomposition Analysis for Density Functional Theory and Density-Functional Tight-Binding with an Evaluation of Energy Fluctuations in Molecular Dynamics.

Pair interaction energy decomposition analysis in the fragment molecular orbital (FMO) method is extended to treat density functional theory (DFT) and density-functional tight-binding (DFTB). Fluctuations of energy contributions are obtained from molecular dynamics simulations. Interactions at the DFT and DFTB levels are compared to the values obtained with Hartree-Fock, second-order Møller-Plesset (MP2), and coupled cluster methods. Hydrogen bonding in water clusters is analyzed. 200 ps NVT molecular dynamics simulations are performed with FMO for two ligands bound to the Trp-cage miniprotein (PDB 1L2Y ); the fluctuations of fragment energies and interactions are analyzed.