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Structure Calculation of Protein Segments Connecting Domains with Defined Secondary Structure: A Simulated Annealing Monte Carlo Combined with Biased Scaled Collective Variables Technique

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Computational Methods for Macromolecules: Challenges and Applications

Part of the book series: Lecture Notes in Computational Science and Engineering ((LNCSE,volume 24))

Abstract

A method for modeling segments of proteins that connect regions with defined secondary structure is illustrated with a study of long segments (8–13 amino acids) that include parts of defined secondary structure motifs. Loop structure calculation can be considered a particular case of this more challenging problem. The new algorithm first finds conformations representative of the segment structure tethered to the protein at one terminus only, and subsequently drives the free end of the segment towards its attachment point using a reversed harmonic constrained simulated annealing scheme. An adjustable force constant drives the free terminal towards the attachment point, using the Monte Carlo (MC) technique of scaled collective variables (SCV). Each segment is initially placed in an extended conformation with the N-terminus covalently bound to the protein, and MC simulated annealing is carried out to find the preferred conformations of the segment. The resulting families of conformations prepare the segment for attachment of the C-terminus. In the second stage a hierarchical protocol drives the segment’s C-terminus towards its final position in the protein. The free C-terminus is attached to a dummy residue, identical to the target residue where the segment will be connected. Successive MC simulations are carried out using the SCV method with increasingly larger values of the harmonic force constant that slowly stabilize the free energy surface to ensure the correct orientation of the segment region with the rest of the system. The performance of the method was evaluated for eight segments in the a-subunit of the G protein transducin for which a high-resolution X-ray crystal structure (2.0 Å) is available. The calculation was performed using the all-atom representation and the CHARMM force field with the electrostatic effects of the solvent described implicitly by the new SCP general continuum model. The segments that are most exposed to solvent are found to be represented best with this method.

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Authors and Affiliations

  1. Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York, New York, 10029, USA

    Sergio A. Hassan, Ernest L. Mehler & Harel Weinstein

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  1. Sergio A. Hassan
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  2. Ernest L. Mehler
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  1. Department of Chemistry, Courant Institute of Mathematical Sciences, New York University, 251 Mercer Street, New York, NY, 10012, USA

    Tamar Schlick  & Hin Hark Gan  & 

  2. Howard Hughes Medical Institute, 251 Mercer Street, New York, NY, 10012, USA

    Tamar Schlick  & Hin Hark Gan  & 

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Hassan, S.A., Mehler, E.L., Weinstein, H. (2002). Structure Calculation of Protein Segments Connecting Domains with Defined Secondary Structure: A Simulated Annealing Monte Carlo Combined with Biased Scaled Collective Variables Technique. In: Schlick, T., Gan, H.H. (eds) Computational Methods for Macromolecules: Challenges and Applications. Lecture Notes in Computational Science and Engineering, vol 24. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-56080-4_9

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  • DOI: https://doi.org/10.1007/978-3-642-56080-4_9

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