Confabulating a crystal lattice for a protein model

Structure prediction has not made crystallography obsolete, but it has however made it easier — here I explore a potential trick that could be used. Under certain conditions, proteins pack in mathematically precise crystalline lattices because the lattice configuration is energetically preferable over being free in the unfriendly crystallisation solution used. Sometimes the protein will refuse to crystallise because either it is happy in solution or it would rather unfold. As a result researchers mutate surface residues to be more hydrophobic or copy the crystal packing interface ("crystal epitope") of a homologue that crystallises. A different (untested) approach could be to design the interface with ProteinMPNN or FastDesign. The catch is that one needs to make a model of the desired supercell to optimise. Here I will discuss how to make it.

Natural products and drug discovery: an evolutionary take

A question (of the nice variety) that students sometimes ask is about the relevance of natural products. The answer is a yes-and-no answer. I like to add to the usual arguments, an evolutionary take, which is two sided. A lot of secondary metabolites made by plants have been evolved to kill you (a mostly herbivore), but your liver has been evolved to be good at destroying them. For drug discovery, this has two opposite effects: the pro is a long list of antibacterial, antifungal and anticancer compounds to use or to adapt, the con is their ADME (absorption, distribution, metabolism, and excretion) properties have frustrated medchemists for decades and decades. Herein, the two faces of this coin are explored not by advocating for or against natural products, but exploring what they mean for medicinal chemistry.