An efficient protocol for obtaining accurate hydration free energies using quantum chemistry and reweighting from molecular dynamics simulations

The non-Boltzmann Bennett (NBB) free energy estimator method is applied to 21 molecules from the blind subset of the SAMPL4 challenge. When NBB is applied with the SMD implicit solvent model, and the OLYP/DZP level of quantum chemistry, highly accurate hydration free energy calculations are obtained with respect to experiment (RMSD = 0.89 kcal·mol⁻¹). Other quantum chemical methods are also tested, and the effects of solvent model, density functional, basis set are explored in this benchmarking study, providing a framework for improvements in calculating hydration free energies. We provide a practical guide for using the best QM-NBB protocols that are consistently more accurate than either pure QM or pure MM alone. In situations where high accuracy hydration free energy predictions are needed, the QM-NBB method with SMD implicit solvent should be the first choice of quantum chemists.     

Impact of calcium on N1 influenza neuraminidase dynamics and binding free energy

The highly pathogenic influenza strains H5N1 and H1N1 are currently treated with inhibitors of the viral surface protein neuraminidase (N1). Crystal structures of N1 indicate a conserved, high affinity calcium binding site located near the active site. The specific role of this calcium in the enzyme mechanism is unknown, though it has been shown to be important for enzymatic activity and thermostability. We report molecular dynamics (MD) simulations of calcium‐bound and calcium‐free N1 complexes with the inhibitor oseltamivir (marketed as the drug Tamiflu), independently using both the AMBER FF99SB and GROMOS96 force fields, to give structural insight into calcium stabilization of key framework residues. Y347, which demonstrates similar sampling patterns in the simulations of both force fields, is implicated as an important N1 residue that can “clamp” the ligand into a favorable binding pose. Free energy perturbation and thermodynamic integration calculations, using two different force fields, support the importance of Y347 and indicate a +3 to +5 kcal/mol change in the binding free energy of oseltamivir in the absence of calcium. With the important role of structure‐based drug design for neuraminidase inhibitors and the growing literature on emerging strains and subtypes, inclusion of this calcium for active site stability is particularly crucial for computational efforts such as homology modeling, virtual screening, and free energy methods. Proteins 2010. © 2010 Wiley‐Liss, Inc.     

A weighted test-area method for calculating surface tension

In this paper, we propose a weighted test-area method to calculate surface tension by incorporating the weighting factor from the Bennett method into the free energy perturbation scheme of the test-area method. This new method was tested by comparing against the results of the Bennett and test-area methods for simulations of square well (SW), Lennard-Jones and point charge fluid models. It is seen that the new method is accurate for all these simulations, giving the same results as the Bennett method, in contrast to the test-area method which cannot calculate the surface tension of a SW fluid. The new method converges as quickly, on the basis of computational time required, as the test-area method and almost twice as quickly as the Bennett method. This combination of speed and accuracy means that the weighted test-area method should be used in preference to the test-area method and Bennett method for surface tension and other macroscopic thermodynamic quantities that can be calculated through perturbation methods.     

Why Procreative Preferences May be Moral – And Why it May not Matter if They Aren't

There has been much argument over whether procreative selection is obligatory or wrong. Rebecca Bennett has recently challenged the assumption that procreative choices are properly moral choices, arguing that these views express mere preferences. This article challenges Bennett's view on two fronts. First, I argue that the Non‐Identity Problem does not show that there cannot be harmless wrongs – though this would require us to abandon the intuitively attractive ‘person‐affecting principle’, that may be a lesser cost than abandoning some more firmly‐held intuition. But, even if we accept Bennett's claim that these choices are not moral, that does not show them to be mere personal preferences. I argue that there is a class of non‐moral ‘categorical preferences’ that have much the same implications as moral preferences. If a moral preference for able‐bodied children is problematic (as Bennett claims), then so is a non‐moral categorical preference. Thus, showing that these preferences are not moral does not show that they are not problematic, since they may still be categorical.     

Radioactive labeling of alpha-bungarotoxin with tritium.

α-[³H] bungarotoxin (Bgt) was prepared by catalytic reduction of ¹²⁵I-labeled α-Bgt with tritium. Specific activities of 10–15 Ci/mmol were attained. The radioactive label was found in tyrosine. Tritiated α-Bgt appears to bind specifically to the cholinergic receptor of diaphragm and to a similar component of cerebral cortex. This specificity and the high specific radioactivity attained provide a useful tool for the study of acetylcholine receptor in brain and other tissues with low receptor concentration.     

Wrongs, preferences, and the selection of children: a critique of Rebecca Bennett's argument against the principle of procreative beneficence

Rebecca Bennett, in a recent paper dismissing Julian Savulescu's principle of procreative beneficence, advances both a negative and a positive thesis. The negative thesis holds that the principle's theoretical foundation - the notion of impersonal harm or non-person-affecting wrong - is indefensible. Therefore, there can be no obligations of the sort that the principle asserts. The positive thesis, on the other hand, attempts to plug an explanatory gap that arises once the principle has been rejected. That is, it holds that the intuitions of those who adhere to the principle are not genuine moral intuitions, but instead simply give voice to mere (non-moral) preferences. This paper, while agreeing that Savulescu's principle does not express a genuine moral obligation, takes issue with both of Bennett's theses. It is suggested that the argument for the negative thesis is either weak or question-begging, while there is insufficient reason to suppose the positive thesis true.     

“The ‘Domestication’ of Heredity: The Familial Organization of Geneticists at Cambridge University, 1895–1910”

In the early years of Mendelism, 1900–1910, William Bateson established a productive research group consisting of women and men studying biology at Cambridge. The empirical evidence they provided through investigating the patterns of hereditary in many different species helped confirm the validity of the Mendelian laws of heredity. What has not previously been well recognized is that owing to the lack of sufficient institutional support, the group primarily relied on domestic resources to carry out their work. Members of the group formed a kind of extended family unit, centered on the Batesons’ home in Grantchester and the grounds of Newnham College. This case illustrates the continuing role that domestic environments played in supporting scientific research in the early 20th century.