Protein Fluctuations and Cavity Changes Relationship.

Abstract

Protein cavities and tunnels are critical for function. Ligand recognition and binding, transport, and enzyme catalysis require cavities rearrangements. Therefore, the flexibility of cavities should be guaranteed by protein vibrational dynamics. Molecular dynamics simulations provide a framework to explore conformational plasticity of protein cavities. Herein, we present a novel procedure to characterize the dynamics of protein cavities in terms of their volume gradient vector. For this purpose, we make use of algorithms for calculation of the cavity volume that result robust for numerical differentiations. Volume gradient vector is expressed in terms of principal component analysis obtained from equilibrated molecular dynamics simulations. We analyze contributions of principal component modes to the volume gradient vector according to their frequency and degree of delocalization. In all our test cases, we find that low frequency modes play a critical role together with minor contributions of high frequency modes. These modes involve concerted motions of significant fractions of the total residues lining the cavities. We make use of variations of the potential energy of a protein in the direction of the volume gradient vector as a measure of flexibility of the cavity. We show that proteins whose collective low frequency fluctuations contribute the most to changes of cavity volume exhibit more flexible cavities.