Internal Cavities and Dynamic Flexibility in Proteases: A Theoretical–Computational Analysis of Their Volumetric Architecture

Jiménez-Castañeda D.; Delgado A.; Alvarado Y.J.; Paz J.L.; González-Paz L. · Revista Politecnica (2026) · DOI: 10.33333/rp.vol57n2.03

Resumen

Internal cavities in proteases are dynamic structural elements that modulate stability, packing density, and conformational flexibility—key features for catalytic activity and allosteric regulation. In this study, we investigated the SARS-CoV-2 main protease (MPRO), papain, and lysozyme through 100 ns molecular dynamics simulations under physiological conditions. Temporal variations of internal cavities, molecular and void volumes, packing factors, and isothermal compressibilities derived from volume fluctuations were quantified. MPRO exhibited the highest variability in cavity number and volume (4–9 per trajectory, 360–880 Å3), revealing a flexible internal network; papain showed intermediate behavior, whereas lysozyme displayed small, stable cavities consistent with its compact fold. Internal compressibility was 3.6–3.7 times higher than the effective one, indicating that cavities account for over 70 % of total volumetric deformability. Cavities act as structural buffers, redistributing local stresses and enabling conformational rearrangements. A direct correlation was observed among cavity number, void volume, and packing factor, defining a functional coupling between internal topology and global flexibility. Overall, this study demonstrates that internal cavities serve as intrinsic volumetric modulators governing the dynamic elasticity of proteases and represent potential allosteric targets for rational inhibitor design based on dynamic and volumetric properties.

Instituciones: Universidad Nacional Mayor de San Marcos