Predicting the clinical subcutaneous absorption rate constant of monoclonal antibodies using only the primary sequence: a machine learning approach.

Subcutaneous injections are an increasingly prevalent route of administration for delivering biological therapies including monoclonal antibodies (mAbs). Compared with intravenous delivery, subcutaneous injections reduce administration costs, shorten the administration time, and are strongly preferred from a patient experience point of view. An understanding of the absorption process of a mAb from the injection site to the systemic circulation is critical to the process of subcutaneous mAb formulation development.

Thirty years of molecular dynamics simulations on posttranslational modifications of proteins.

Posttranslational modifications (PTMs) are an integral component to how cells respond to perturbation. While experimental advances have enabled improved PTM identification capabilities, the same throughput for characterizing how structural changes caused by PTMs equate to altered physiological function has not been maintained. In this Perspective, we cover the history of computational modeling and molecular dynamics simulations which have characterized the structural implications of PTMs.

Antibody apparent solubility prediction from sequence by transfer learning.

Developing therapeutic monoclonal antibodies (mAbs) for the subcutaneous administration requires identifying mAbs with superior solubility that are amenable for high-concentration formulation. However, experimental screening is often material and labor intensive. Here, we present a strategy (named solPredict) that employs the embeddings from pretrained protein language modeling to predict the apparent solubility of mAbs in histidine (pH 6.

How do antiporters exchange substrates across the cell membrane? An atomic-level description of the complete exchange cycle in NarK.

Major facilitator superfamily (MFS) proteins operate via three different mechanisms: uniport, symport, and antiport. Despite extensive investigations, the molecular understanding of antiporters is less advanced than that of other transporters due to the complex coupling between two substrates and the lack of distinct structures. We employ extensive all-atom molecular dynamics simulations to dissect the complete substrate exchange cycle of the bacterial NO/NO antiporter, NarK.

FingerprintContacts: Predicting Alternative Conformations of Proteins from Coevolution.

Proteins are dynamic molecules which perform diverse molecular functions by adopting different three-dimensional structures. Recent progress in residue-residue contacts prediction opens up new avenues for the de novo protein structure prediction from sequence information. However, it is still difficult to predict more than one conformation from residue-residue contacts alone.

Characterizing Conformational Dynamics of Proteins Using Evolutionary Couplings.

Understanding of protein conformational dynamics is essential for elucidating molecular origins of protein structure-function relationship. Traditionally, reaction coordinates, i.e.