De novo protein design has recently emerged as an attractive approach for studying the structure and function of proteins. This approach critically tests our understanding of the principles of protein folding; only in de novo design must one truly confront the issue of how to specify a protein's fold and function. If we truly understand proteins, it should be possible to design receptors, enzymes, and ion channels from scratch. Further, as this understanding evolves and is further refined, it should be possible to design proteins and biomimetic polymers with properties unprecedented in nature.

/pdf/de-novo-design-and-structural-characterization-of-proteins-4i28otfhhl.pdf

De Novo Design and Structural Characterization of Proteins and Metalloproteins

https://www.cell.com/structure/pdf/S1359-0278(96)00046-6.pdf

The concept of a random coil: Residual structure in peptides and denatured proteins

The pharmaceutical industry, driven by an increasing need to deliver new and more effective medicines to patients, is increasingly turning to the use of engineered biocatalysts for both lead generation of active compounds and the sustainable manufacture of active pharmaceutical ingredients. Advances in enzyme discovery, high-throughput screening and protein engineering have substantially expanded the available biocatalysts, and consequently, many more synthetic transformations are now possible. Enzymes can be fine-tuned for practical applications with greater speed and likelihood of success than before, thereby leading to greater predictability and confidence when scaling up these processes. Coupled with a greater awareness of which reactions are suitable for biocatalysis (for example, biocatalytic retrosynthesis), new chemoenzymatic and multi-enzyme processes have been designed and applied to the synthesis of a range of important pharmaceutical target molecules. Increasingly, researchers are exploring opportunities for using immobilized biocatalysts in flow conditions. In this Review, we discuss some of the key drivers and scientific developments that are expanding the application of biocatalysis in the pharmaceutical industry and highlight potential future developments that likely will continue to increase the impact of biocatalysis in drug development. Engineered biocatalysts are increasingly being used for both the identification and manufacture of active pharmaceutical ingredients. Here, the authors review key developments that are expanding the use of biocatalysis in the pharmaceutical industry.

Extending the application of biocatalysis to meet the challenges of drug development

A database has been compiled documenting the peptide conformations and geometries from 70 diverse proteins refined at 1.75 A or better. Analysis of the well-ordered residues within the database shows phi, psi-distributions that have more fine structure than is generally observed. Also, clear evidence is presented that the peptide covalent geometry depends on conformation, with the interpeptide N-C alpha-C bond angle varying by nearly +/-5 degrees from its standard value. The observed deviations from standard peptide geometry are greatest near the edges of well-populated regions, consistent with strain occurring in these conformations. Minimization of such hidden strain could be an important factor in thermostability of proteins. These empirical data describing how equilibrium peptide geometry varies as a function of conformation confirm and extend quantum mechanics calculations, and have predictive value that will aid both theoretical and experimental analyses of protein structure.

/pdf/experimentally-observed-conformation-dependent-geometry-and-57n0jab0cf.pdf

Experimentally observed conformation-dependent geometry and hidden strain in proteins.

http://compbio.berkeley.edu/people/brenner/pubs/brenner-1997-cosb.pdf

Population statistics of protein structures: lessons from structural classifications

Understanding enzyme function evolution from a computational perspective.

Supplementary Structural Models (SARS-CoV-2 Spike-RBD:ACE2 complex and TMPRSS2) - SARS-CoV-2 spike protein predicted to form complexes with host receptor protein orthologues from a broad range of mammals

Following a short summary of some of the principal features of folded proteins, the results of two complementary studies of protein structure are presented, the first concerned with the factors which influence secondary structure propensity and the second an analysis of protein topology. In an attempt to deconvolute the physical contributions to secondary structure propensities, we have calculated intrinsic phi, psi propensities, derived from the coil regions of proteins. Comparison of intrinsic phi, psi propensities with their equivalent secondary structure values show correlations for both helix and strand. This suggests that the local dipeptide, steric and electrostatic interactions have a major influence on secondary structure propensity. We then proceed to inspect the distribution of protein domain folds observed to date. Several folds occur very commonly, so that 46% of the current non-homologous database comprises only nine folds. The implications of these results for protein folding are discussed.

Protein Folds: Towards Understanding Folding from Inspection of Native Structures

Macromolecular structure information and databases

The goal of our research is to increase our understanding of how biology works at the molecular level, with a particular focus on how enzymes evolve their functions through adaptations to generate new specificities and mechanisms. FunTree (Sillitoe and Furnham, Nucleic Acids Res 44:D317-D323, 2016) is a resource that brings together sequence, structure, phylogenetic, and chemical and mechanistic information for 2340 CATH superfamilies (Sillitoe et al., Nucleic Acids Res 43:D376-D381, 2015) (which all contain at least one enzyme) to allow evolution to be investigated within a structurally defined superfamily.We will give an overview of FunTree's use of sequence and structural alignments to cluster proteins within a superfamily into structurally similar groups (SSGs) and generate phylogenetic trees augmented by ancestral character estimations (ACE). This core information is supplemented with new measures of functional similarity (Rahman et al., Nat Methods 11:171-174, 2014) to compare enzyme reactions based on overall bond changes, reaction centers (the local environment atoms involved in the reaction), and the structural similarities of the metabolites involved in the reaction. These trees are also decorated with taxonomic and Enzyme Commission (EC) code and GO annotations, forming the basis of a comprehensive web interface that can be found at http://www.funtree.info . In this chapter, we will discuss the various analyses and supporting computational tools in more detail, describing the steps required to extract information.

/pdf/exploring-enzyme-evolution-from-changes-in-sequence-194tojps58.pdf

Christine M. Orengo

Papers

Understanding enzyme function evolution from a computational perspective.

Supplementary Structural Models (SARS-CoV-2 Spike-RBD:ACE2 complex and TMPRSS2) - SARS-CoV-2 spike protein predicted to form complexes with host receptor protein orthologues from a broad range of mammals

Protein Folds: Towards Understanding Folding from Inspection of Native Structures

Macromolecular structure information and databases

Exploring Enzyme Evolution from Changes in Sequence, Structure, and Function.