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Protein dynamics and the immunological evolution of molecular recognition.

ABSTRACT: While it is accepted that protein flexibility plays a role in protein folding, catalysis, and molecular recognition, few techniques are capable of the rigorous measurement of protein motions required to quantify flexibility. Three-pulse photon echo shift spectroscopy can be used to measure the time scale of protein motions, and we have used this technique, along with steady-state spectroscopy and binding and structural data, to examine the immunological evolution of protein flexibility in an anti-fluorescein antibody. Two light chain somatic mutations increase affinity for fluorescein by 12-fold but also significantly affect flexibility. Specifically, a rigidification of the protein is seen in each of three observable motions; two slower motions undergo decreased amplitudes of displacement, by 3- and 20-fold, respectively, in response to an applied force, and the distribution associated with the amplitude of a faster motion is narrowed upon somatic mutation. The somatic mutations appear to rigidify the antibody-fluorescein complex by more strongly anchoring fluorescein to the protein and by more tightly packing the complex. The data demonstrate that in addition to affinity, antibody dynamics are systematically manipulated during affinity maturation, and they imply that the evolution of protein flexibility may be a central component of the immune response. The results also reflect the type of protein rigidification that may be important for other biological interactions, such as protein-protein, protein-ligand or protein-drug, and enzyme-substrate recognition.

SUBMITTER: Jimenez R

PROVIDER: S-EPMC374325 | biostudies-other | 2004 Mar

REPOSITORIES: biostudies-other

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Protein dynamics and the immunological evolution of molecular recognition.

Jimenez Ralph R Salazar Georgina G Yin Jun J Joo Taiha T Romesberg Floyd E FE

Proceedings of the National Academy of Sciences of the United States of America 20040304 11

While it is accepted that protein flexibility plays a role in protein folding, catalysis, and molecular recognition, few techniques are capable of the rigorous measurement of protein motions required to quantify flexibility. Three-pulse photon echo shift spectroscopy can be used to measure the time scale of protein motions, and we have used this technique, along with steady-state spectroscopy and binding and structural data, to examine the immunological evolution of protein flexibility in an ant ...[more]

PMID: 15001706

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Project description:Molecular dynamics (MD) simulation of biologically relevant processes at realistic time scale and atomistic precision is generally limited by prohibitively large computational cost, due to its restriction of using an ultrashort integration time step (1-2 fs). A popular numerical recipe to reduce the associated computational burden is adopting schemes that would allow relatively longer-time-step for MD propagation. Here, we explore the perceived potential of one of the most frequently used long-time-step protocols, namely the hydrogen mass repartitioning (HMR) approach, in alleviating the computational overhead associated with simulation of the kinetic process of protein-ligand recognition events. By repartitioning the mass of heavier atoms to their linked hydrogen atoms, HMR leverages around twofold longer time step than regular simulation, holding promise of significant performance boost. However, our probe into direct simulation of the protein-ligand recognition event, one of the computationally most challenging processes, shows that long-time-step HMR MD simulations do not necessarily translate to a computationally affordable solution. Our investigations spanning cumulative 176 μs in three independent proteins (T4 lysozyme, sensor domain of MopR, and galectin-3) show that long-time-step HMR-based MD simulations can catch the ligand in its act of recognizing the native cavity. But, as a major caveat, the ligand is found to require significantly longer time to identify buried native protein cavity in an HMR MD simulation than regular simulation, thereby defeating the purpose of its usage for performance upgrade. A molecular analysis shows that the longer time required by a ligand to recognize the protein in HMR is rooted in faster diffusion of the ligand, which reduces the survival probability of decisive on-pathway metastable intermediates, thereby slowing down the eventual recognition process at the native cavity. Together, the investigation stresses careful assessment of pitfalls of long-time-step algorithms before attempting to utilize them for higher performance for biomolecular recognition simulations.

Dataset Information

Protein dynamics and the immunological evolution of molecular recognition.

Publications

Protein dynamics and the immunological evolution of molecular recognition.

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