Progress and challenges in predicting protein interfaces

Abstract

The majority of biological processes are mediated via protein–protein interactions. Determination of residues participating in such interactions improves our understanding of molecular mechanisms and facilitates the development of therapeutics. Experimental approaches to identifying interacting residues, such as mutagenesis, are costly and time-consuming and thus, computational methods for this purpose could streamline conventional pipelines. Here we review the field of computational protein interface prediction. We make a distinction between methods which address proteins in general and those targeted at antibodies, owing to the radically different binding mechanism of antibodies. We organize the multitude of currently available methods hierarchically based on required input and prediction principles to provide an overview of the field.

Predicting Protein–Protein Interaction Sites Using Sequence Descriptors and Site Propensity of Neighboring Amino Acids

“…Specifically, an amino acid residue is to be considered as a PPI interface site provided at least one of its atoms is within 5 Å or less from any other atom of another amino acid residue. This definition is in accordance with previous reports [77,78] and has been used by other studies, as well [12]. …”

“…Existing methods for predicting PPI sites can be summarized into two categories: The template-based and the intrinsic-based approaches [12]. The template-based approaches involve a comparison of proteins with and without structural data.…”

“…Other methods [18,19] incorporate predicted structural information (e.g., surface accessibility and secondary structure). A recent review [12] suggested that, other than the two types of information mentioned above, sequence-based methods must investigate alternative sources of information to further improve the prediction accuracy.…”

Physical epistatic landscape of antibody binding affinity

“…Affinity maturation also produces broadly neutralizing antibodies that target conserved regions of the pathogen, of particular importance for vaccine design against fast evolving viruses [3]. Despite extensive experimental and theoretical work, the key determinants of antibody specificity and evolvability are still poorly understood, mainly because the sequence-to-affinity relationship is difficult to measure comprehensively or to predict computationally [4].A major confounding factor in characterizing the sequence dependence of any protein function, including affinity, is the pervasiveness of epistasis, the phenomenon by which different mutations interact with each other [5]. Theory [6][7][8] and genomic data [9] suggest that interand intragenic epistasis plays a major role in molecular evolution, by constraining the set of accessible evolutionary trajectories towards adapted phenotypes [10][11][12][13][14], enhancing evolvability through stabilizing mutations [15,16], or slowing down adaptation by the law of diminishing returns [17,18].…”

“…Affinity maturation also produces broadly neutralizing antibodies that target conserved regions of the pathogen, of particular importance for vaccine design against fast evolving viruses [3]. Despite extensive experimental and theoretical work, the key determinants of antibody specificity and evolvability are still poorly understood, mainly because the sequence-to-affinity relationship is difficult to measure comprehensively or to predict computationally [4].…”