Before revision: Machupo virus (MACV) is a New World arenavirus that is currently emerging from a rodent reservoir into the human population. For New World arenaviruses, it is known that transferrin receptor binding is a major determinate of host range variation. To better understand the relationship between the virus and its human host, we used a structure-based computational model to interrogate the effects of mutations in the interfacebetween the MACV spike glycoprotein ( MACVGP) and the Human transferrin receptor (hTfR1) . Existing computational methods to probe protein-protein interactions perform poorly with non-alanine mutations and on the flexible loops encountered in many host-virus interactions.
After revision: Existing computational methods to predict protein--protein interaction affinity often perform poorly in important test cases. In particular, the effects of multiple mutations, non-alanine substitutions, and flexible loops are difficult to predict with available tools and protocols. We present here a new method to interrogate affinity differences resulting from mutations in a host-virus protein--protein interface. Our method is based on extensive non-equilibrium all-atom simulations: We computationally pull the machupo virus (MACV) spike glycoprotein ( MACVGP) and the Human transferrin receptor (hTfR1) . Existing computational methods to probe protein-protein interactions perform poorly with non-alanine mutations and on the flexible loops encountered in many host-virus interactions.