Dynamics, a Powerful Component of Current and Future in Silico Approaches for Protein Design and Engineering

Abstract

Computational prediction has become an indispensable aid in the processes of engineering and designing proteins for various biotechnological applications. With the tremendous progress in more powerful computer hardware and more efficient algorithms, some of in silico tools and methods have started to apply the more realistic description of proteins as their conformational ensembles, making protein dynamics an integral part of their prediction workflows. To help protein engineers to harness benefits of considering dynamics in their designs, we surveyed new tools developed for analyses of conformational ensembles in order to select engineering hotspots and design mutations. Next, we discussed the collective evolution towards more flexible protein design methods, including ensemble-based approaches, knowledge-assisted methods, and provable algorithms. Finally, we highlighted apparent challenges that current approaches are facing and provided our perspectives on their further development.

Exploring the Cold-Adaptation Mechanism of Serine Hydroxymethyltransferase by Comparative Molecular Dynamics Simulations

“…Although it has been suggested that the increased flexibility in the regions that are involved in the catalytically relevant motions can reduce the activation enthalpy, such regions in pSHMT still remain to be identified in future work. Interestingly, it has been found that the increased protein surface flexibility in several cold-adapted enzymes is directly related to the reduced activation enthalpy compared to the warm-active counterparts [ 34 , 36 , 37 ], implying that the surface mobility could act to modulate the conformational changes occurring during catalysis through the interaction network and correlated motions [ 38 , 39 , 40 ]. For pSHMT, it is possible that the positive effect (i.e., reduced activation enthalpy) arising from the considerably increased flexibility in the surface loops ( Figure 3 ) could over-counteract the negative effect (i.e., reduced activation entropy) arising from the increased flexibility in the regions not involved in the catalytic motions, thus resulting in a lower activation free energy and explaining its increased catalytic activity compared to mSHMT.…”

Alpha-Carbonic Anhydrases from Hydrothermal Vent Sources as Potential Carbon Dioxide Sequestration Agents: In Silico Sequence, Structure and Dynamics Analyses

“…Although the analysis of static multimeric models gave an adequate representation of the important interactions within the structures, proteins often have a number of conformations in vivo, thus necessitating their simulation and analyses [101]. MD simulations allowed sampling of a wide range of these conformations, as shown by the root mean square deviation (RMSD) Kernel density estimation (KDE) plots in Figure 4.…”

Functionalization of a symmetric protein scaffold: Redundant folding nuclei and alternative oligomeric folding pathways

“…Protein design offers an infinite possibility of novel protein structures and functionalities with diverse application in the areas of novel therapeutics, diagnostics, sensors, materials, etc. One common approach is computational protein design targeting enzyme engineering, protein specificity, cellular pathway control, and higher‐order protein assembly 1–6 . However, as a single step, computational design has the challenging requirement of solving at least three design problems simultaneously, including (a) protein foldability (i.e., folding kinetics requirements), (b) protein stability (i.e., thermodynamic requirements), and (c) the accommodation of specific function (with potential structural dynamics requirements).…”