Scientific objectivity was not a problem in the early days of molecular biology. However, relativism seems to have invaded some areas of the field, damaging the objectivity of its analyses. This review reports on the status of this issue by investigating a number of cases.

Over the last decade Japanese researchers have taken the lead in the emerging discipline of molecular robotics. This new technology aims to produce artificial molecular systems that can adapt to changes in the environment, self-organize and evolve. This paper explores the question of how to stimulate responsible research and innovation in the field of molecular robotics technologies. For this, we first draw lessons from earlier societal responses in Japan to emerging technologies, such as genetic engineering, nanotechnology, synthetic biology and genomic research. Next we describe various real-time technology assessment (TA) activities on molecular robotics in Japan to depict the state-of-the-art of the academic and public debate on the social aspects of molecular robotics. Lessons from earlier societal responses to emerging technologies demonstrated three potential challenges: finding and involving the ‘right’ experts and stakeholders, keeping regulations up to date, and getting scientists and citizens involved in science communication. A literature review, ‘future workshop’ and scenario workshop raised a number of ethical, social, political and cultural issues, and addressed desirable and undesirable scenarios for the next few decades. Twitter text mining analysis indicates that the level of attention, knowledge and awareness about molecular robots among a broader audience is still very limited. In conclusion, we identify four activities crucial to enable responsible innovation in molecular robotics—getting to grips with the speed of the development of molecular robotics, monitoring related technical trends, the establishment of a more stable TA knowledge base, and a sustained interaction between molecular roboticists and social scientists.

Intravenous anesthetic barbitals act on the GABA_A receptor, and this receptor is the principal molecular target of loss of consciousness. Their action and side effects differ according to the enantiomer. Elucidation of their enantiomeric action is essential for a safe anesthetic agent. This study investigates molecular mechanisms of discrimination of enantiomeric barbital in the binding site of the GABA_A receptor. Amobarbital, (R)-, (S)-pentobarbital, and (R)-, (S)-isobarbital bonded to the TM2-TM2’ transmembrane domain (TMD), i.e., the propofol binding site. There was a 2.9 kcal mol^_-1 difference in enantiomeric pentobarbital bindings. Pentobarbital discrimination in the TM2-TM2’ TMD site was caused not only by the barbital ring’s hydrogen-bond, but also by steric fittings of the methyl-group adjacent to the chiral carbon atom.

The statistical properties of the inter-fragment interaction energy matrix of the fragment molecular orbital method are analyzed using the random matrix theory. The eigenvalue and eigenvector distributions, the inverse participation ratio, and the unfolded eigenvalue statistics are compared with the corresponding random matrix ensemble. Cluster analysis of the fragments with strong correlations is presented using the inverse participation ratio of the random matrix theory.

Here we present a novel technique that utilizes a supporting inorganic film for MD simulations of flat-shaped DNA origami structures in explicit solvent. The number of atoms is typically over 16 million including water molecules. By utilizing a GPU capable simulation engine, we have addressed conformational changes of a DNA origami structure under normal ionic strength and deionized water conditions up to the order of one nanosecond simulation time. Our results demonstrate that DNA origami configuration undergoes a continual growth in the absence of cations, while it is not the case for normal ionic strength. Statistical analysis of helix forms for these DNA origami structures reveals that not only cations but also water permittivity contributed to the maintenance of B-DNA helix form during the stretching motion. These results will provide key features in designing molecular robots as assembly of DNA origami structural components such as scaffolds, connectors and channels.

We developed a portable code for dissipative particle dynamics (DPD) simulations. This Fortran program named CAMUS has a couple of notable features. One is the omission of constructing the so-called neighboring particles list, providing a sizable speed-up per step and also a near linear scaling of costs with respect to the number of particles. The other is an easy inclusion of additional specific (such as 1-3 and 1-5 Morse bonding) interactions which are crucial in describing protein structures. The formations of α-helix and β-sheet through DPD were then demonstrated. CAMUS is freely available at the GitHub site.

We have applied Google’s TensorFlow deep learning toolkit to recognize the visualized results of the fragment molecular orbital (FMO) calculations. Typical protein structures of α-helix and β-sheet provide some characteristic patterns in the two-dimensional map of inter-fragment interaction energy termed as IFIE-map (Kurisaki et al., Biophys. Chem. 130 (2007) 1). A thousand of IFIE-map images with labels depending on the existences of α-helix and β-sheet were prepared by employing 18 proteins and 3 non-protein systems and were subjected to training by TensorFlow. Finally, TensorFlow was fed with new data to test its ability to recognize the structural patterns. We found that the characteristic structures in test IFIE-map images were judged successfully. Thus the ability of pattern recognition of IFIE-map by TensorFlow was proven.

Curcumin can bind to tubulin and inhibit the formation of tubulin polymer, which contributes to the formation of microtubule. Binding sites of curcumin on the α- and β-tubulin heterodimer were predicted by a molecular docking study to ascertain probable causes for the observed anti-microtubule effects of curcumin. However, the specific interactions between curcumin and the tubulins have yet to be elucidated at an electronic level. We here investigated the binding properties between curcumin and α- or β-tubulin of Plasmodium falciparum, using ab initio fragment molecular orbital (FMO) calculations, in order to reveal the preferable binding sites of curcumin on these tubulins. The results were compared with those for some microtubule destabilizing drugs evaluated by the same method to confirm the efficiency of curcumin as an inhibitor to the tubulins. Our ab initio FMO calculations might provide useful information for proposing novel therapeutic agents with significant binding affinity to both the α- and β-tubulins.

The chirality of a compound affects its biochemical and pharmaceutical properties. It was found that the binding affinity between vitamin D receptor (VDR) and its ligand depends significantly on the chirality of the ligand. To elucidate the reason for this dependence, we here investigated the specific interactions between VDR and two types of ligands with different chirality, using ab initio fragment molecular orbital (FMO) calculations. The FMO results reveal that the part of ligand with different chirality interacts strongly with the imidazole ring of histidine side-chain in VDR, and that the binding affinity between VDR and the ligands depends on the protonation state of the histidine. This finding indicates the possibility that ligands with different chirality can assign the protonation state of VDR histidine residues existing near the ligand.

We are presently continuing to perform biomolecular chemical simulations for Burkholderia cepacia lipase (BCL) and Candida antarctica lipase typeB (CALB) to predict their enantioselectivity and reactivity toward various organic compounds. Here, we describe molecular dynamics (MD) and fragment molecular orbital (FMO) calculations on the complexes of CALB with primary and secondary alcohol esters. For esters with high enantioselectivity, the fast-reacting enantiomer of esters is located near the active site of CALB, whereas the slow-reacting enantiomer of esters moves away from the active site of CALB. On the other hand, for the esters with low enantioselectivity, we found that both (R)- and (S)-enantiomers of esters remain the active site of CALB. The FMO computations indicate that for the esters with high enantioselectivity, each fast-reacting enantiomer shows strong interactions with some particular amino acid residues, including Thr40, whereas for the esters with low enantioselectivity, both (R)- and (S)-enantiomers interact with identical amino acid residues including Thr40. It is predictable that Thr40 in CALB plays an important role in the chiral recognition of enantiomers through lipase-catalyzed biotransformations.

Adverse effects induced by the duplication of drugs with anticholinergic effects are a problem among elderly people who take many drugs. Various anticholinergic rating scales have been published and are applied clinically to evaluate a patient’s anticholinergic burden; however, there are some problems with these scales, such as drugs that are assessed differ ently between scales. We aimed to construct a method to more correctly distinguish between drugs with and without anticholinergic effects and to understand the properties of drugs that have anticholinergic effects. We constructed a model for identifying anticholinergic effects via a decision tree, using descriptors indicating the physicochemical properties of the drugs. The best split yielded a decision tree with 46 branches (area under the receiver operating charac teristic curve = 0.99). However, only seven branches, defined by six descriptors: ASA_P, GCUT_PEOE_0, opr_brigid, PEOE_VSA+1, GCUT_SLOGP_0, vsa_pol (related to van der Waals surface areas, partial charges, and molecule structures), were required to identify drugs with anticholinergic effects. This result suggests a relationship between the hydropho bic interactions of drugs and the muscarinic receptor. In this study, we constructed a model to predict whether drugs have anticholinergic effects, and obtained essential physicochemical information on the drugs to distinguish their anticholinergic effects. It is our hope that these findings provide useful information for predicting anticholinergic effects of drugs in clinical settings.

The fragment molecular orbital (FMO) method is recently attracting attention as a method of calculating the electronic state of macromolecular systems. To enhance the speed of the FMO method, it is necessary to apply an approximation in which SCF calculations are neglected for distant fragment (monomer) pairs (dimers) and instead the electrostatic interactions between the two monomers are calculated. This approximation is called the dimer-es approximation. The accuracy and speed brought by the dimer-es approximation depend on the minimum threshold distance between two atoms to apply the approximation. This threshold distance given in unit of van der Waals radii is named “L_dimer-es”. In this communication, we examined dependence of HF and MP2 electron correlation energy errors on “L_dimer-es”, and it is preferable to calculate FMO4-HF and FMO4-MP2 for calculation of FMO-HF and FMO-MP2 of side chain-split peptides with L_dimer-es=2.0.

In the cyclohexane derivatives, the equatorial conformer, having less steric repulsion of hydrogen atoms adjacent to substituent, is dominant over the axial conformer. This is a normal stereochemical requirement. In hexose, containing oxygen atoms in the ring, however, α-anomer (with axial substituent) is more stable than β-anomer (with equatorial substituent) and it is called the anomeric effect. Why does this phenomenon, which is not compatible with the stereochemical intuition (but still widely accepted), happen at all? It has been more than 60 years since Edward reported it, but the root cause has not yet become clear. At present, the most popular explanation for the anomeric effect is that it is due to the interaction between a lone pair of electrons on oxygen and the anti-bonding orbital (σ*) of C-R bond. Contrary to popular belief, we demonstrate that this explanation does not hold.

The fashionable but stereotypic thinking on the concept of the so-called “hydrophobic bond” has been examined in light of criticisms raised by many scientists: Hildebrand, Shinoda, Israelachvili, and so on. The author's comments are given on the harmful influence of the concept of “hydrophobic bond” in chemistry and biochemistry. In my opinion, this concept can be considered as a myth in modern science.