An artificial neural network approach to improving the correlation between protein energetics and the backbone structure

Computational approaches to modeling protein structures have made significant advances over the past decade. However, the current limitation in modeling protein structures is to produce protein structures consistently below the limit of 6 Å compared to their native structure. Therefore, improvement of protein structures consistently below the 6 Å limit using simulation of biophysical forces is of significant interest. Current protein force fields such as those implemented in CHARMM, AMBER, and NAMD have been deemed complete, yet their use in ab initio approaches to protein structure determination has been unsuccessful. Here, we introduce a new approach in evaluation of protein structures based on analysis of energy profiles produced by the SCOPE software package. The latest version of SCOPE produces a hydrogen bond profile that is substantially more informative than a single hydrogen bond energy value. We demonstrate how analysis of SCOPE's energy profile by an artificial neural network shows a significant improvement compared to the traditional force‐based approaches to evaluation of structures. The artificial neural network based analysis of SCOPE's energy profile showed identification of structures to within the range of 1.5–3.0 Å of the native structure. These results have been obtained by testing structures in the same Homology, Topology, Architecture, or Class of the CATH family.

[1]  Laxmikant V. Kalé,et al.  Scalable molecular dynamics with NAMD , 2005, J. Comput. Chem..

[2]  Ellen J. Bass,et al.  Improving pairwise sequence alignment accuracy using near-optimal protein sequence alignments , 2010, BMC Bioinformatics.

[3]  W. Kabsch,et al.  Dictionary of protein secondary structure: Pattern recognition of hydrogen‐bonded and geometrical features , 1983, Biopolymers.

[4]  David C. Jones,et al.  CATH--a hierarchic classification of protein domain structures. , 1997, Structure.

[5]  G. Kane.  Parallel Distributed Processing: Explorations in the Microstructure of Cognition, vol 1: Foundations, vol 2: Psychological and Biological Models , 1994 .

[6]  L. Lebioda,et al.  Effects of ligand binding and conformational switching on intracellular stability of human thymidylate synthase. , 2004, Biochimica et biophysica acta.

[7]  Holger Gohlke,et al.  The Amber biomolecular simulation programs , 2005, J. Comput. Chem..

[8]  Jianpeng Ma,et al.  CHARMM: The biomolecular simulation program , 2009, J. Comput. Chem..

[9]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[10]  A G Murzin,et al.  SCOP: a structural classification of proteins database for the investigation of sequences and structures. , 1995, Journal of molecular biology.

[11]  D. Baker,et al.  An orientation-dependent hydrogen bonding potential improves prediction of specificity and structure for proteins and protein-protein complexes. , 2003, Journal of molecular biology.

[12]  Homayoun Valafar,et al.  An Artificial Neural Network Based Approach for Identification of Native Protein Structures Using an Extended Forcefield , 2011, 2011 IEEE International Conference on Bioinformatics and Biomedicine.

[13]  J. Skolnick,et al.  Further Evidence for the Likely Completeness of the Library of Solved Single Domain Protein Structures , 2011 .

[14]  S. Irausquin,et al.  SCOPE : An Open-Source , C + + Implementation for Calculation of Protein Energetics from First Principles , 2011 .

[15]  Charles D Schwieters,et al.  The Xplor-NIH NMR molecular structure determination package. , 2003, Journal of magnetic resonance.

[16]  M. Karplus,et al.  CHARMM: A program for macromolecular energy, minimization, and dynamics calculations , 1983 .

[17]  Kenneth Levenberg.  A METHOD FOR THE SOLUTION OF CERTAIN NON – LINEAR PROBLEMS IN LEAST SQUARES , 1944 .

[18]  C. Anfinsen.  Principles that govern the folding of protein chains. , 1973, Science.

[19]  Gautam R. Desiraju,et al.  The Weak Hydrogen Bond: In Structural Chemistry and Biology , 1999 .

[20]  C Sander,et al.  Mapping the Protein Universe , 1996, Science.

[21]  C. Dobson.  Protein folding and misfolding , 2003, Nature.

[22]  K. Wüthrich,et al.  Torsion angle dynamics for NMR structure calculation with the new program DYANA. , 1997, Journal of molecular biology.

[23]  J. Skolnick,et al.  Why not consider a spherical protein? Implications of backbone hydrogen bonding for protein structure and function. , 2011, Physical chemistry chemical physics : PCCP.