title: Computational alanine scanning with linear scaling semiempirical quantum mechanical methods.
abstract: Alanine scanning is a powerful experimental tool for understanding the key interactions in protein-protein interfaces. Linear scaling semiempirical quantum mechanical calculations are now sufficiently fast and robust to allow meaningful calculations on large systems such as proteins, RNA and DNA. In particular, they have proven useful in understanding protein-ligand interactions. Here we ask the question: can these linear scaling quantum mechanical methods developed for protein-ligand scoring be useful for computational alanine scanning? To answer this question, we assembled 15 protein-protein complexes with available crystal structures and sufficient alanine scanning data. In all, the data set contains Delta Delta Gs for 400 single point alanine mutations of these 15 complexes. We show that with only one adjusted parameter the quantum mechanics-based methods outperform both buried accessible surface area and a potential of mean force and compare favorably to a variety of published empirical methods. Finally, we closely examined the outliers in the data set and discuss some of the challenges that arise from this examination.
authors.affiliation: Pfizer Inc, 865 Ridge Road, Monmouth Junction, New Jersey 08543, USA. djrdiller@gmail.com
authors.forename: David J
authors.initials: DJ
authors.lastname: Diller
authors.forename: Christine
authors.initials: C
authors.lastname: Humblet
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Zhang
authors.forename: Lance M
authors.initials: LM
authors.lastname: Westerhoff
mesh_terms: D000409:Alanine / Q000737:chemistry*; D019295:Computational Biology / Q000379:methods*; D030562:Databases, Protein; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D011506:Proteins / Q000737:chemistry*; D011789:Quantum Theory; D013499:Surface Properties; D014867:Water / Q000737:chemistry
chemical_list: D050505:Mutant Proteins; D011506:Proteins; D014867:Water; D000409:Alanine