Some dogmas of religion
London, 1906
Abstract
Predicting the binding mode of flexible polypeptides to proteins is an important task that falls outside the domain of applicability of most small molecule and protein−protein docking tools. Here, we test the small molecule flexible ligand docking program Glide on a set of 19 non-α-helical peptides and systematically improve pose prediction accuracy by enhancing Glide sampling for flexible polypeptides. In addition, scoring of the poses was improved by post-processing with physics-based implicit solvent MM- GBSA calculations. Using the best RMSD among the top 10 scoring poses as a metric, the success rate (RMSD ≤ 2.0 Å for the interface backbone atoms) increased from 21% with default Glide SP settings to 58% with the enhanced peptide sampling and scoring protocol in the case of redocking to the native protein structure. This approaches the accuracy of the recently developed Rosetta FlexPepDock method (63% success for these 19 peptides) while being over 100 times faster. Cross-docking was performed for a subset of cases where an unbound receptor structure was available, and in that case, 40% of peptides were docked successfully. We analyze the results and find that the optimized polypeptide protocol is most accurate for extended peptides of limited size and number of formal charges, defining a domain of applicability for this approach.
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If it is suggested that there is no evidence that the universe is working towards a good end, the doubter is reminded of the limitations of his intellect, and on account of this is exhorted to banish his doubts from his mind, and to believe firmly that the universe is directed towards a good end. And stronger instances can be found. An apologist may admit, for example, that for our intellects the three facts of the omnipotence of a personal God, the benevolence of a personal God, and the existence of evil, are not to be reconciled. But we are once more reminded of the feebleness of our intellects. And we are invited to assert, not only that our conclusions may be wrong, not only that the three elements may possibly be reconciled, but that they are reconciled. There is evil, and there is an omnipotent and benevolent God.
This line of argument has two weaknesses. The first is that it will prove everything—including mutually incompatible propositions—equally well. It will prove as easily that the universe is tending towards a bad end as that it is tending towards a good one. There may be as little evidence for the pessimistic view as for the optimistic. But if our intellects are so feeble that the absence of sufficient evidence in our minds is no objection to a conclusion in the one case, then a similar absence can be no objection to a conclusion in the other. Nor can we fall back on the assertion that there is less evidence for the pessimistic view than for the optimistic, and that, therefore, we should adopt the latter. For if our intellects are too feeble for their conclusions to be trusted, our distrust must apply equally to their conclusion on the relative weight of the evidence in the two cases.
So far as punishment is vindictive, it makes a wicked man miserable, without making him less wicked, and without making any one else less wicked or less miserable. It can only be justified on one of two grounds. Either something else can be ultimately good, besides the condition of conscious beings, or the condition of a person who is wicked and miserable is better, intrinsically and without regard to the chance of future amendment, than the condition of a person who is wicked without being miserable. If either of these statements is true—to me they both seem patently false—then vindictive punishment may be justifiable both for determinists and indeterminists. If neither of them is true, it is no more justifiable for indeterminists than it is for determinists.